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WO2025224168A1 - Dérivés d'arylsulfone et de sulfanone utilisés en tant que modulateurs du récepteur de l'orexine - Google Patents

Dérivés d'arylsulfone et de sulfanone utilisés en tant que modulateurs du récepteur de l'orexine

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WO2025224168A1
WO2025224168A1 PCT/EP2025/061059 EP2025061059W WO2025224168A1 WO 2025224168 A1 WO2025224168 A1 WO 2025224168A1 EP 2025061059 W EP2025061059 W EP 2025061059W WO 2025224168 A1 WO2025224168 A1 WO 2025224168A1
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methyl
sulfonyl
pyrrolidine
amide
carboxylic acid
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Olivier Bezencon
Bibia Heidmann
Andreas MUEHLEMANN
Davide Pozzi
Sylvia Richard-Bildstein
Romain Siegrist
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Idorsia Pharmaceuticals Ltd
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Idorsia Pharmaceuticals Ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel aryl sulfone and sulfanone 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 agonists of the orexin-2 receptor (hereinafter also referred to as OX2R), and particularly as agonists of the human orexin-2 receptor (hereinafter also referred to as hOX2R).
  • the orexin system (also known as hypocretin system) was discovered in 1998 by two independent research groups and is composed of 2 neuropeptides and 2 receptors (de Lecea L et al.; The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity; Proc Natl Acad Sci U S A. 1998, 95(1 ):322-7; Sakurai T et al.; Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior; Cell. 1998, 92(5): 1 page following 696).
  • Orexin A and orexin B are neuropeptides specifically expressed in a small population of neurons of the lateral, dorsomedial and perifornical hypothalamus. They are proteolytically derived from a single precursor prepro-orexin peptide. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide. Orexins bind to two G-protein-coupled receptors (orexin- 1 receptor (OX1R) and orexin-2 receptor (OX2R)) widely expressed throughout the brain. While OX-A binds to both receptors with similar affinity, OX-B binds preferentially to OX2R. The wide distribution of orexin fibers and receptors in many parts of the brain suggests that orexins have multiple functions.
  • the orexin system is recognized as being crucial for the stability of wakefulness and the regulation of vigilance in accordance with various physiological processes (de Lecea L; Hypocretins and the neurobiology of sleep-wake mechanisms; Prog Brain Res. 2012, 198: 15-24; Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci. 2007, 8(3): 171 -81 ; Scammell TE et al.; Neural Circuitry of Wakefulness and Sleep; Neuron. 2017, 93(4):747-765). Orexin neurons are primarily active during wakefulness (Lee MG et al.; Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle; J Neurosci.
  • wake-promoting neuronal populations such as the histaminergic neurons of the tuberomammillary nucleus, noradrenergic neurons of the locus coeruleus, serotoninergic neurons of the dorsal raphe, dopaminergic neurons in the ventral tegmental area and cholinergic neurons in the basal forebrain and the pedunculopontine and laterodorsal tegmental nuclei.
  • wake-promoting regions of the brain predominantly express OX1R or OX2R, or both (for review see (Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci.
  • orexin neurons integrate a variety of signals related to internal or external environment (e.g. emotion, light/dark cycles, sleep pressure, energy balance) and send information to a variety of neuronal systems to adjust the arousal level to the one necessary for an appropriate behavioral response (Inutsuka A et al.; The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions; Front Endocrinol (Lausanne). 2013, 4: 18).
  • signals related to internal or external environment e.g. emotion, light/dark cycles, sleep pressure, energy balance
  • narcolepsy type 1 a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions), is linked to a deficiency in the orexin system (Chemelli RM et al.; Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation; Cell. 1999, 98(4):437-51 ; Lin L et al.; The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene; Cell.
  • narcolepsy type 1 has been shown to be caused by the loss of orexin-producing neurons (Peyron C et al.; A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains; Nat Med. 2000, 6(9):991 -7) and low OX-A level in the CSF can be used as specific biological measure for the diagnosis (Dauvarri Y et al.; Narcolepsy and Other Central Hypersomnias; Continuum (Minneap Minn). 2017, 23(4, Sleep Neurology):989-1004).
  • intracerebroventricular (i.c.v.) injections of OX-A in rats or mice increased wakefulness and markedly reduced both non-rapid eye movement (NREM) and REM sleep (Piper DC et al.; The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats; Eur J Neurosci. 2000, 12(2)726-30; Huang ZL et al.; Arousal effect of orexin A depends on activation of the histaminergic system; Proc Natl Acad Sci U S A. 2001 , 98(17):9965- 70).
  • orexin receptors activation of orexin receptors is a promising therapeutic approach for disease associated with difficulties maintaining wakefulness with patients complaining of: feelings of excessive sleepiness; episodes of inadvertently falling asleep, including sleep attacks (episodes of falling asleep without prodromal symptoms of drowsiness); a prolonged main sleep episode that is unrefreshing; recurrent naps in the same day; and sleep inertia (prolonged difficulty waking up, with irritability, automatic behavior, or confusion).
  • sleep disorders such as the disorders of hypersomnolence.
  • ICSD-3 3 rd edition
  • idiopathic hypersomnia Kleine-Levin syndrome
  • hypersomnia due to a medical disorder hypersomnia due to a medication or substance
  • hypersomnia associated with psychiatric disorder and insufficient sleep syndrome.
  • Narcolepsy is supposed to be the result of an autoimmune disorder which specifically destroy orexin-producing neurons.
  • symptoms of narcolepsy can occur during the course of other neurologic disorders and be caused by the underlying condition, e.g. inherited disorders (such as Prader-Willi syndrome, Niemann-Pick C disease, or myotonic dystrophy), tumors or head trauma (particularly when the hypothalamus area is involved) (Kanbayashi T et al.; The pathophysiologic basis of secondary narcolepsy and hypersomnia; Curr Neurol Neurosci Rep.
  • orexin deficiency in the CSF and narcolepsy-like symptoms have been observed in patients with neuromyelitis optica, multiple sclerosis (Kanbayashi T et al.; The pathophysiologic basis of secondary narcolepsy and hypersomnia; Curr Neurol Neurosci Rep. 2011, 11 (2):235-41 ; Kanbayashi T et al.; Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications; Arch Neurol.
  • Guillain- Barre syndrome (Nishino S et al.; CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies; Neurology. 2003, 61 (6):823-5), or anti-Ma2 encephalitis (Overeem S et al.; Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis; Neurology. 2004, 62(1): 138-40).
  • EDS can also be observed in circadian rhythm sleep-wake disorders such as for example delayed sleep-wake phase disorder, shift work or jet lag disorder and result from a misalignment between the body clock and social requirements (Sateia MJ; International classification of sleep disorders-third edition: highlights and modifications; Chest. 2014, 146(5): 1387-1394; Vogel KD et al.; Excessive Daytime Sleepiness: A Clinical Review; Mayo Clin Proc. 2021 , 96(5): 1288-1301 ). It is specially the case when the patient needs to be awake but their alertness level secondary to their internal body clock is at its nadir.
  • EDS is accompanying disorders such as obesity, diabetes, depression and objective sleep disturbances such as sleep apnea (Fernandez-Mendoza J et al.; Natural history of excessive daytime sleepiness: role of obesity, weight loss, depression, and sleep propensity; Sleep. 2015, 38(3):351-60).
  • sleep apnea apnea
  • OSA obstructive sleep apnea
  • dysregulation of the orexin system could play a role in the pathogenesis of this disorder (Wang W et al.; Orexin: a potential role in the process of obstructive sleep apnea; Peptides. 2013, 42:48-54).
  • fatigue is a lack of energy ("an overwhelming sense of tiredness, a feeling of exhaustion") with a reduced ability to perform physical activities that would have previously been easily accomplished. It may be accompanied by mental fatigue with poor concentration and memory, but it is not generally associated with inappropriate episodes of sleep during the day. It is observed in a number of disorders including infections, chronic inflammatory diseases, cancer and neurodegeneration. It is suggested that a dysregulation of the orexin system could contribute to fatigue.
  • Traumatic brain injury can induce disorders of consciousness (DOC) such as syndromes of coma, vegetative state, and minimally conscious state (O'Donnell JO et al.; Challenges and demand for modeling disorders of consciousness following traumatic brain injury; Neurosci Biobehav Rev. 2019, 98:336-346).
  • Consciousness is a complex state including arousal and awareness and the ascending reticular activating system (ARAS) is known to play an essential role in maintaining consciousness (Edlow BL et al.; Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders; J Neuropathol Exp Neurol. 2012, 71 (6):531- 46).
  • the ARAS is a complex and diffuse network of neuronal fibers that connects the brainstem reticular formation (such as the nuclei containing serotoninergic, noradrenergic, dopaminergic, cholinergic and glutamatergic neurons) with nonspecific thalamic nuclei, the basal forebrain, hypothalamus, and the cerebral cortex. Impairment of the ARAS can cause loss of consciousness following TBI (Jang SH et al.; The Relation Between Loss of Consciousness, Severity of Traumatic Brain Injury, and Injury of Ascending Reticular Activating System in Patients With Traumatic Brain Injury; Am J Phys Med Rehabil. 2019, 98(12): 1067-1071).
  • Monoaminergic drugs acting by increasing for instance dopaminergic levels, norepinephrine levels and acetylcholine levels could have some beneficial impacts on DOC.
  • the orexin system Given its projections to the wake-promoting system and its contribution to the stabilization of wakefulness/arousal, the orexin system is well placed to support and regulate consciousness.
  • abnormally low level of OX-A in the CSF was reported (Baumann CR et al.; Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury; Neurology. 2005, 65(1 ): 147- 9).
  • OX-A facilitated the recovery of arousal in a cardiac arrest- induced coma rat model
  • a cardiac arrest- induced coma rat model Koenig MA et al.; Intraventricular orexin-A improves arousal and early EEG entropy in rats after cardiac arrest; Brain Res. 2009, 1255:153-61; Modi HR et al.; Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation; PLoS One. 2017, 12(9):e0182707).
  • Orexin agonists could then provide beneficial effects following cardiac failure.
  • OX-A did not only accelerate arousal and behavior recovery, but it also had some anti-inflammatory effects.
  • OX-A improved the neurofunctional outcomes and mitigated brain edema (Li T et al.; Orexin A alleviates neuroinflammation via OXR2/CaMKKbeta/AMPK signaling pathway after ICH in mice; J Neuroinflammation. 2020, 17(1):187). It is suggested that OX-A was beneficial because of its anti-inflammatory effects.
  • orexins facilitate the emergence from anesthetic-induced unconsciousness with anesthesia being either intraperitoneal or gas anesthesia and that inhibiting the orexin signaling delays the emergence (Zhang LN et al.; Orexin-A facilitates emergence from propofol anesthesia in the rat; Anesth Analg. 2012, 115(4)789-96; Kelz MB et al.; An essential role for orexins in emergence from general anesthesia; Proc Natl Acad Sci U S A.
  • Orexins Besides stabilizing wakefulness, the orexins system seems to play a role in the regulation of many other functions such as energy homeostasis, learning and memory, stress/emotion, reward, and pain.
  • the orexin system is involved in the regulation of feeding behaviors and energy homeostasis.
  • Orexin neurons are sensitive to glucose, leptin and ghrelin with high concentrations of glucose and leptin inhibiting orexinergic neurons, while low concentrations of glucose and ghrelin exciting them (Diano S et al.; Fasting activates the nonhuman primate hypocretin (orexin) system and its postsynaptic targets; Endocrinology.
  • mice exhibit obesity despite a significant lower calorie consumption which can be explained, to some extent, by a lower energy expenditure (Zhang S et al.; Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy; J Physiol. 2007, 581 (Pt 2):649-63).
  • the prevalence of obesity is also increased in narcoleptic patients (Mohammad! S et al.; Metabolic profile in patients with narcolepsy: a systematic review and meta-analysis; Sleep Med. 2021 , 81 :268-284).
  • the orexin system seems to play a role in learning and memory processes.
  • On one hand given its recognized role for the stability of wakefulness and the regulation of vigilance in accordance with various physiological processes (de Lecea L; Hypocretins and the neurobiology of sleep-wake mechanisms; Prog Brain Res. 2012, 198:15-24; Sakurai T; The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness; Nat Rev Neurosci. 2007, 8(3): 171 -81 ; Scammell TE et al.; Neural Circuitry of Wakefulness and Sleep; Neuron. 2017, 93(4)747-765), it will contribute to the sustained arousal level necessary to learn.
  • mice showed that OX-A could contribute to the increase hippocampal plasticity associated with the consolidation of social recognition memory (Yang L et al.; Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice; J Neurosci.
  • Cognitive impairment is a common feature of several neuropsychiatric/neurological disorders and of age/age- related dementias. Age is also affecting the orexin system. Indeed in both human and animals, loss of orexin neurons is reported (for review (Nixon JP et al.; Sleep disorders, obesity, and aging: the role of orexin; Ageing Res Rev. 2015, 20:63-73)). Interestingly, age-related impairments in attentional performance could be improved in rats via intranasal administration of OX-A (Galva CB et al.; Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction; Brain Res.
  • the orexin system plays a role in behaviours needing motivation (Mahler SV et al.; Motivational activation: a unifying hypothesis of orexin/hypocretin function; Nat Neurosci. 2014, 17(10): 1298-303). And motivation (the psychological drive underlying goal-directed behaviour) is important to organize psychological and physiological processes leading to adaptive behaviours. Motivated behaviours support, for example, food seeking, coordinated stress response and the development of coping strategy. Dysregulation of those processes can lead to neuropsychiatric disorders in which orexin receptor agonists could provide beneficial effects.
  • stimulation of OX2R promoted coping responses in a decision-making test during social stress in mice (in this test: promotion of escape behaviour)
  • Staton CD et al. Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression; Neuropharmacology. 2018, 143:79-94
  • Stimulation of OX2R also increased resilience to social stress (i.e. social novelty seeking)
  • Staton CD et al.; Orexin 2 receptor stimulation enhances resilience, while orexin 2 inhibition promotes susceptibility, to social stress, anxiety and depression; Neuropharmacology. 2018, 143:79-94).
  • Anhedonia one of the key symptoms of depression, can be described as the failure to experience pleasure or pursue gratification and encompasses reward-associated disorders such as perturbation in decision-making and motivational drive.
  • Anhedonia symptoms evoke a dysregulation of brain reward processing in which an alteration of the orexin system function could play a role (Coccurello R; Anhedonia in depression symptomatology: Appetite dysregulation and defective brain reward processing; Behav Brain Res. 2019, 372: 112041).
  • Several preclinical and clinical studies have shown a link between dysregulation of the orexin system and depression (Khairuddin S et al.; Dysregulation of the orexinergic system: A potential neuropeptide target in depression; Neurosci Biobehav Rev.
  • Wistar-Kyoto rats which demonstrate depressive-like behaviours, OX-A immunoreactivity and prepro-orexin mRNA levels were reduced in the hypothalamus compared to Wistar rats (Taheri S et al.; Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats; Neuroreport. 2001 , 12(3):459- 64).
  • animals models of depression induced by chronic, inescapable stressors such as the social defeat model of chronic stress, downregulation of orexin neurotransmission was observed (Lutter M et al.; Orexin signaling mediates the antidepressant-like effect of calorie restriction; J Neurosci.
  • Orexin neurons project to many brain regions involved in the regulation of pain, including the spinal dorsal horn, the ventrolateral periaqueductal gray, the rostral ventromedial medulla or the trigeminal caudate nucleus (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23):9996-10015).
  • Administration of orexin into the spinal cord or centrally in brain areas associated with the descending pain regulatory circuits reduces nociceptive responses in animal models of inflammatory pain and in chronic neuropathic pain models.
  • intrathecal injections or local injections in pain-regulating brain areas of orexin receptor antagonists modulate pain responses (for review see: (Kang X et al.; Research progress on the mechanism of orexin in pain regulation in different brain regions; Open Life Sci. 2021 , 16(1):46-52)).
  • pain threshold is lower in orexin knockout mice following peripheral local inflammation (Watanabe S et al.; Persistent pain and stress activate pain-inhibitory orexin pathways; Neuroreport. 2005, 16(1):5-8).
  • lower CSF orexin levels were reported in patients suffering from cluster headache (Barloese M et al.; Reduced CSF hypocretin-1 levels are associated with cluster headache; Cephalalgia.
  • US 2014/0051700 discloses cyclic guanidinyl OX2R agonists useful for enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.
  • WO 2014/198880 discloses 2-(2-aminophenoxy)-3-chloronaphthalene-1, 4-dione compounds having orexin 2 receptor agonist activities, and their use therapeutic active substances for the treatment of conditions mediated by agonizing the orexin 2 receptor.
  • WO 2017/135306 discloses substituted piperidine compounds having an orexin type 2 receptor agonist activity, and their use as prophylactic or therapeutic agents for narcolepsy.
  • WO 2018/164191 discloses substituted pyrrolidine compounds having an orexin type 2 receptor agonist activity.
  • WO 2019/117148 discloses sulfonamide derivatives showing an orexin receptor agonist activity.
  • WO 2019/027003, WO 2019/027058, WO 2020/004537/US 2021/198240, WO 2020/122092 and WO 2020/122093 disclose heterocyclic compounds having orexin type 2 receptor agonist activity.
  • WO 2020/167706 discloses 5-alkyl pyrrolidine orexin receptor agonists.
  • Orexin receptor agonists are further reported in WO 2018/164192, WO 2021/106975, WO 2020/158958, US 2021/0155636, WO 2020/167701 , WO 2021/026047, WO 2021/107023, WO 2016/133160, WO 2021/065893, and WO 2019/191327.
  • Selected indolyl and pyrrolyl aryl sulfones are disclosed as anti-HIV agents (Silvestri R et al., Novel Indolyl Aryl Sulfones Active against HIV-1 Carrying NNRTI Resistance Mutations: Synthesis and SAR Studies, J. Med. Chem. 2003, 46:2482-2493; Ragno R et al., Docking and 3-D QSAR Studies on Indolyl Aryl Sulfones.
  • Certain benzene sulfonamide derivatives are disclosed as selective potassium channel activators (Mattmann M et al., Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1- tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K v 7.1 (KCNQ1) potassium channel activator, 2012, 22(18):5936-5941).
  • WO 2005/097162 describes selected aryl sulfonyl derivatives as steroid sparing agents.
  • WO 00/04892 discloses certain hydroxamic acid-comprising benzene sulfonyl derivatives as MMP inhibitors.
  • US 2001/0056184 describes pipecolinic acid derivatives as MMP inhibitors.
  • WO 97/18194 and US6225311 discloses certain hydroxamic acidcomprising benzene sulfonamide derivatives as MMP and TACE inhibitors, respectively.
  • WO 2005/030728 describes selected aryl sulfonamide derivatives as MMP inhibitors.
  • WO 2013/020440 discloses certain aryl sulfonamide derivatives as 11-p hydroxy steroid dehydrogenase type I inhibitors.
  • EP0469984 refers to N-sulfonyl- indoline derivatives as binding to vasopressin and oxytocin receptors.
  • WO 2014/098098 describes selected aryl sulfonamide antagonists of TRPA1.
  • JP 2006124387 referring to MCH receptor antagonists, discloses certain sulfone-comprising pyridine derivatives.
  • WO 2012/025877 discloses certain proline sulfonamide derivatives as orexin receptor antagonists.
  • WO 2008/038251 describes selected non-peptide antagonists of orexin receptors. Further orexin receptor antagonists are described in: WO 2002/051838, WO 2004/004733, WO 2004/085403, WO 2005/118548, WO 2008/020405, WO 2008/026149, WO 2008/065626, WO 2008/078291, WO 2008/081399, WO 2008/087611, WO 2008/117241,
  • WO 2010/131191 WO 2010/131192, WO 2012/063207, and WO 2012/110986.
  • the following compounds are known as chemical library compounds: 1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-piperidinecarboxamide (CAS no. 2174271-82-8); 1 -([1,1'-biphenyl]-2-ylsulfonyl)-N-methyl-2-piperidinecarboxamide (CAS no. 2421462-12-4); 1-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-pyrrolidinecarboxamide (CAS no.
  • a first aspect of the invention relates to compounds of the Formula (I) wherein
  • Ring B is a 6-membered aromatic ring, wherein independently:
  • X 1 represents N or CR B2 , wherein R B2 represents hydrogen, halogen (especially fluoro), or (Ci-3)alkyl (especially methyl), and X 2 represents CH; [notably such X 1 represents CH, C-CH3, or N]; or X 1 represents CH and X 2 represents N; and
  • R B3 represents: OR 01 , wherein R 01 represents (C2-s)alkyl (especially ethyl, propyl, isopropyl, sec-butyl, or isobutyl) that is substituted with zero, one or two (Ci)fluoroalkyl (especially difluoromethyl or trifluoromethyl); wherein R 01 contains a total of at least 3 carbon atoms; [notably OR 01 represents propoxy, isopropoxy, sec-butoxy, isobutoxy, (1 , 1 -d if I uoropropan-2-y l)-oxy , (3, 3-d ifl uoro-2, 2-d I methy l-propy l)-oxy , (1 ,1 ,1 -trifl uoropropan-2- yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1 ,1 , 1 ,3, 3, 3- hexafluoropropan-2-
  • ⁇ R N1 represents:
  • (C2-5)alkyl especially propyl, isopropyl, sec-butyl, or fert-butyl); wherein said (C2-5)alkyl is unsubstituted, or mono- or di-substituted (especially unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (Ci)fluoroalkyl (especially trifluoromethyl), (C ⁇ cycloalkyl (especially cyclopropyl), and (Ci-3)alkoxy (especially methoxy); or
  • NR N1 R N2 represents isopropyl-amino, sec-butyl-amino, terf-butyl-amino, (l-methyl-cyclopropyl)-amino, (l-cyclopropyl-ethyl)-amino, (1 -methoxy propan-2-yl)-ami no, (1, 1 ,1 -tr if I uoropropan-2-y l)-ami no, (1 , 1 ,1 -trifl uorobu tan-2 -y I )-am I no, (1 -cy clopropy I-2, 2, 2- trifluoroethyl)-amino, (isopropyl)-(methyl)-amino, (ferf-butyl)-(methyl)-amino, (cyclopropyl)- (methyl)-amino, diethyl-amino, (ethyl)-(isopropy
  • R N1 and R N2 together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), (Ci.
  • R N2 represents pyrrolidin-1 -yl, piperidin-1 - yl, 2-methylpyrrolidin-1-yl, 2-(trifluoromethyl)pyrrolidin-1-yl, 2-methylpiperidin-1-yl, 3- fluoropiperidin-1-yl, 4-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2- (methoxymethyl)piperidin-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2,3-dimethylpyrrolidin-1-yl, 2-ethyl-5- methylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1 -yl, azepan-1-yl, 3-methylmorpholin-4-y
  • R N1 and R N2 together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom;
  • group NR N1 R N2 represents 2-azabicyclo[2.2.1]heptan-2-yl, 7- azabicyclo[2.2.1 heptan-7-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, or 3-oxa-8- azabicyclo[3.2.1]octan-8-yl)]; or a saturated or mono-unsaturated monocyclic (C5-z)cycloalkyl (notably cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1 -yl, cycloheptyl, or cyclohept-1-en-1-yl); wherein said (C4-6)cycloal
  • X 3 represents 0 or NR N3 , wherein R N3 represents hydrogen, (Ci-s)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom (especially oxetanyl or tetrahydrofuranyl), a 5-membered saturated bridged bicyclic cycloalkyl (especially bicyclo[1.1.1]pentanyl), phenyl, or pyridinyl; [notably X 3 represents 0, N-methyl, NH, or N-cyclopropyl]; and
  • X 4 represents CH or N such that: when X 4 represents CH, Ring A represents a monocyclic (C5-6)cycloalkan-diyl; or when X 4 represents N, Ring A represents: • a 4- to 7-membered (notably 5- to 7-membered) saturated monocyclic heterocycloalkan-diyl comprising X 4 , and zero or one further ring heteroatom selected from 0 or S (especially azetidin-diyl, pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl; in particular pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, or oxazolidin-diyl); wherein said saturated heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents
  • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X 4 , and zero or one ring oxygen atom (notably hexahydrocyclopenta[b]pyrrol-1 (2/7),2-diy I, hexahydro-4/-/- furo[3,2-b]pyrrol-4,5-diyl, azabicyclo[2.1.1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, or azaspiro[2.4]heptan-diyl; in particular azabi cyclo [2.1 .1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, azaspiro[2.4]heptan-diyl,
  • R 1 represents: hydrogen; or (Ci-3)alkyl (especially methyl or ethyl); wherein said (Ci-3)alkyl is unsubstituted, or mono-substituted with (Ci-3)alkoxy (especially methoxy); and
  • R 2 represents: (Ci-6)alkyl (especially linear (C2-e)alkyl or branched (C3-e)alkyl); wherein said (Ci-e)alkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently halogen (especially fluoro or chloro) or (Ci-3)alkoxy (especially methoxy); or -(CH2) q -Cy 1 ; wherein q is 0 or 1 (especially 0) and Cy 1 represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl
  • a 5- or 6-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S
  • said 5- or 6-membered heterocycle is pyrrolidine, piperidine, thiazolidine, thiomorpholine, or morpholine
  • said 5- or 6-membered heterocycle is unsubstituted, or mono-, di- or tri-substituted
  • the substituents are independently selected from the group consisting of: hydroxy, (Ci-3)fluoroalkyl (especially trifluoromethyl), halogen (especially fluoro), (Ci ⁇ alkyl (especially methyl), (Ci-3)alkyl-(Ci-3)alkoxy (especially methoxymethyl or ethoxymethyl), ethynyl, and (Ci-3)alkoxy (especially methoxy or ethoxy);
  • such heterocycle represents 2-(methoxymethyl)pyrrolidin-1 -yl, 2-(ethoxymethyl
  • a 7- to 11-membered (especially 8-membered) saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms (notably said heterocycle is 2- azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan-
  • 6-yl 2-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan- 2-yl, 1-oxa-6-azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[5.5]undecan-8-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 1 ,4-dioxa-8-azaspiro[4.6]undecan-8- yl, 8-oxa-2-azaspiro[4.5]decan-2-yl, or 8-azaspiro[4.5]decan-8-yl; in particular said heterocycle is 6- azaspiro[2.5]octan-6-yl); wherein said heterocycle is unsubstitute
  • an 8- to 10-membered saturated or mono-unsaturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom
  • said heterocycle is hexahydrocyclopenta[c]pyrrol-2(1 /-/)-yl, octahy d roq ui nol I n-1 (2/7)-y I , hexahy d rofu ro[3, 2-c] py rid I n- 5(4/-/)-yl, or 1 ,3,3a, 4,7, 7a-hexahydro-2/-/-isoindol-2-yl); or
  • a 7- to 9-membered (especially 7- to 8-membered) saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom
  • said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; in particular said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl or 8
  • a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms (notably 2-azaadamantan-2-yl or 2-oxa-6-azaadamantan-6-yl); with the exception of the following compounds: 1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-2-piperidinecarboxamide (CAS no. 2174271-82-8); 1 -([1 ,1 '-biphenyl]-2-ylsulfonyl)-N-methyl-2-piperidinecarboxamide (CAS no.
  • N-cyclopropyl-1 -[[2-(5-isoxazolyl)phenyl]sulfonyl]-2-pyrrolidinecarboxamide (CAS no. 1957026-44-6); 1-([1 J T-biphenyl]-2-ylsulfonyl)-N-propyl-2-pyrrolidinecarboxamide (CAS no. 1101182-03-9); 1-[(4-ethoxy-3-pyridinyl)sulfonyl]-2-(methoxymethyl)-N-methyl-2-pyrrolidinecarboxamide (CAS no.
  • N,N-diethyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 1444098-57-0); N-(1 , 1-dimethylethyl)-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-4-thiazolidinecarboxamide (CAS no. 2175321- 07-8); N-cyclopropyl-3-[[2-(5-isoxazolyl)phenyl]sulfonyl]-N-methyl-4-thiazolidinecarboxamide (CAS no.
  • 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 further encompass compounds with one or more double bonds which may be present in Z- or E-configuration and/or compounds with substituents at a ring system which may be present, relative to each other, in cis- or transconfiguration.
  • 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 more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration, but where one (or more) of said stereogenic or asymmetric centers is not explicitly designated as (R)- or (S)-, it is understood that said stereogenic or asymmetric center may be in (R)- or (S)-configuration.
  • stereogenic or asymmetric center may be in (R)- or (S)-configuration.
  • Such compound name or generic structure is understood to encompass the compound I generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center.
  • 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.
  • 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.
  • any defined relative configuration with regard to the two or more centers is present, such centers are denominated with (R*,R*) or (R*,S*) nomenclature indicating in the first instance that the respective centers are either (R,R) or (S,S), and in the second instance that the respective centers are either (R,S) or (S,R), in each case encompassing any mixture of these stereoisomers including the racemate. It is understood that explicitly designated (R)- or (S)-configuration, undesignated or designated (RS)-configuration, and relative (R*,R*)- or (R*,S*)- configuration can co-exist in one and the same molecule and are to be interpreted accordingly.
  • the compound (2R*,4R*)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide encompasses enantiomerically enriched (2R,4R)-1-[2-(Ethyl- isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N- methyl-amide, (2S,4S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-4-methyl-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide,
  • a particular compound (or generic structure) is designated as Sa- or Ra-stereoisomer (i.e., designating an conformational isomer, or atropisomer, arising from a hindered rotation around a single bond), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form.
  • 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 I 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 I the entirety of the respective other stereoisomers.
  • the present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of Formula (I) according to embodiments 1) to 27), 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 (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) 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.
  • the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) 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 the 4,4-difluorocyclohexyl group.
  • the compounds of Formula (I) may contain tautomeric forms. Such tautomeric forms are encompassed in the scope of the present invention. In case tautomeric forms exist of a certain residue, and only one form of such residue is disclosed or defined, the other tautomeric form(s) are understood to be encompassed in such disclosed residue.
  • 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 27), 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 I or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.
  • halogen means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.
  • 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 six 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 (Ci-e)alkyl group contains from one to six carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fert-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, and 3,3-dimethyl-butyl.
  • 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.
  • R B1 representing (Ci-3)alkyl are methyl, ethyl, and isopropyl.
  • An example of R B2 representing (Ci-3)alkyl is methyl.
  • R 01 representing (C2-5)alkyl are ethyl, propyl, isopropyl, sec-butyl, and isobutyl; such R 01 representing (C ⁇ alkyl may be unsubstituted or substituted as explicitly defined.
  • R N1 representing (Ci-s)alkyl are methyl, ethyl, and isopropyl.
  • R N2 representing (C ⁇ alkyl are propyl, isopropyl, sec-butyl, and fert-butyl; such R N2 representing (C2-5)alkyl may be unsubstituted or substituted as explicitly defined.
  • Examples of (Ci-s)alkyl as substituent of a group R B3 are methyl and ethyl, and especially methyl.
  • Examples of R N3 representing (Ci-s)alkyl are methyl and ethyl.
  • An example of (Ci-s)alkyl as substituent of Ring A is methyl.
  • Examples of R 1 representing (Ci-3)alkyl are methyl and ethyl; such R 1 representing (Ci-3)alkyl may be unsubstituted or substituted as explicitly defined.
  • R 2 representing (Ci-e)alkyl are methyl, ethyl, propyl, isopropyl, 2,2-dimethyl-propyl, n-butyl, 3- methyl-butyl, 3,3-dimethyl-butyl, and fert-butyl; such R 2 representing (Ci ⁇ alkyl may be unsubstituted or substituted as explicitly defined.
  • Examples of (Ci-s)alkyl as substituent of a group Cy 1 are methyl and isopropyl.
  • An example of (Ci-3)alkyl as substituent of a group Cy 2 or Cy 3 is methyl.
  • (Ci ⁇ )alkyl as substituent of a 5- or 6- membered saturated monocyclic heterocycle formed by R 1 and R 2 , together with the nitrogen to which they are attached, is methyl.
  • 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 (Ci-4)alkoxy 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, secbutoxy, and tert-butoxy. Preferred is methoxy.
  • An example of R B1 representing (Ci -3)alkoxy is methoxy.
  • An example of (Ci-3)alkoxy as substituent of R B3 is methoxy.
  • An example of (Ci-3)alkoxy as substituent of Ring A is methoxy.
  • An example of (Ci-3)alkoxy as substituent of a group R 1 is methoxy.
  • An example of (Ci-3)alkoxy as substituent of a group R 2 is methoxy.
  • Examples of (Ci-3)alkoxy as substituent of a 5- to 6-membered saturated monocyclic heterocycle formed by R 1 and R 2 , together with the nitrogen to which they are attached, are methoxy and ethoxy.
  • Examples of (Ci-3)al koxy as substituent of a 7- to 9-membered saturated bridged bicyclic heterocycle formed by R 1 and R 2 , together with the nitrogen to which they are attached, are methoxy and ethoxy.
  • (Ci-4)alkoxy-(C2-4)alkyl is methoxy methyl.
  • 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.
  • Preferred are (Ci-3)fluoroalkyl groups such as trifluoromethyl.
  • An example of R B1 representing (Ci-3)fluoroalkyl is trifluoromethyl.
  • Examples of (Ci)fluoroalkyl as substituent of R 01 are difluoromethyl and trifluoromethyl.
  • An example of (Ci)fluoroalkyl as substituent of R N2 representing a (C ⁇ alkyl is trifluoromethyl.
  • Examples of (Ci-2)fl uoroalky I as substituent of a 5- to 7-membered saturated monocyclic heterocycle formed by R N1 and R N2 , together with the nitrogen to which they are attached, are trifluoromethyl and 2,2,2- trifluoroethyl.
  • An example of (Ci-3)fluoroalkyl as substituent of R B3 representing phenyl or a 5- or 6-membered heteroaryl is trifluoromethyl.
  • Examples of (Ci-3)fluoroalkyl as substituent of Cy 1 are difluoromethyl and trifluoromethyl.
  • An example of (Ci ⁇ fluoroalkyl as substituent of Cy 2 is difluoromethyl.
  • fluoroalkoxy used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x -y)fluoroalkoxy refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2 -fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.
  • R B3 representing OR 01 , wherein R 01 represents (C2- s)alkyl substituted with one or two (Ci)fluoroalkyl, and wherein R 01 contains a total of at least 3 carbon atoms; are (1, 1-difluoropropan-2-yl)oxy, 3,3-difluoro-2,2-dimethyl-propoxy, (1 ,1, 1-trifluoropropan-2-yl)oxy, (4,4,4- trifluorobutan-2-yl)oxy, (1 ,1 , 1 ,3, 3, 3- hexafluoropropan-2-yl)oxy.
  • An example of (Ci-3)fluoroalkyl as substituent of R B3 representing phenyl or 5- or 6-membered heteroaryl is trifluoromethoxy.
  • hydroxy refers to a group -OH.
  • cyano refers to a group -ON.
  • (Cx-Y)alkylidene (x and y each being an integer), 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 x to y carbon atoms, wherein said alkyl group is linked to the rest of the molecule via a double bond.
  • (Cx-Y)alkenyl (x and y each being an integer), 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 x to y carbon atoms, wherein said alkyl group contains a double bond and wherein said alkyl group is linked to the rest of the molecule via a single bond.
  • An example of a (C2-4)alkenyl is vinyl group -CHOH2.
  • ethynyl refers to a group -C CH.
  • 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 )cycloalky I (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms.
  • a (Cs ejcycloalky I group contains from three to six carbon atoms.
  • (C x.y )cycloalkyl refers to a saturated monocyclic cycloalkyl group as defined before, containing x to y carbon atoms.
  • monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • R B1 representing a monocyclic (C3-4)cycloalkyl are cyclopropyl and cyclobutyl.
  • R N2 representing a monocyclic (C ⁇ cycloalkyl is cyclopropyl; such R N2 representing a monocyclic (C ⁇ cycloalkyl may be unsubstituted or substituted as explicitly defined.
  • An example of (C ⁇ cycloalkyl as substituent of R N2 representing (C ⁇ alkyl is cyclopropyl.
  • Examples of R B3 representing a saturated monocyclic (C4-6)cycloalkyl are cyclopentyl, cyclohexyl, and cycloheptyl; such R B3 representing a saturated monocyclic (C4-6)cycloalkyl may be unsubstituted or substituted as explicitly defined.
  • R B3 represents phenyl or a 5- or 6-membered heteroaryl
  • R N3 representing a monocyclic (C3-6)cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl.
  • Cx-y mono-unsaturated monocyclic (Cx-y)cycloalkyl
  • x and y each being an integer
  • R B3 representing a mono-unsaturated monocyclic (C5-
  • cycloalkyl are cyclopent-1 -en-1-yl, cyclohex-1 -en-1-yl, and cyclohept-1-en-1-yl; such R B3 representing a monounsaturated monocyclic (Cs-zjcycloalkyl may be unsubstituted or substituted as explicitly defined.
  • (C x -y)cycloalkan-diyl or "monocyclic (C x -y)cycloalkan-diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to bivalently bound cycloalkyl group, as defined before, containing x to y carbon atoms.
  • Ring A represents a monocyclic (Cs-ejcycloalkan-diyl
  • the points of attachment of said (C5-6)cycloalkan-diy I in Formula (I) are on X 4 and on a carbon atom neighboring X 4 ; examples are cyclopentane-1 ,2-diyl and cyclohexane-1 ,2-diyl; such monocyclic (C5-6)cycloalkan-diyl may be unsubstituted or substituted as explicitly defined.
  • saturated bicyclic (C x-y )spirocycloalkyl or "saturated spiro bicyclic (C x.y ) cycloalkyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated spiro-bicyclic hydrocarbon ring containing x to y carbon atoms.
  • R 1 representing a saturated bicyclic (C6-8)spirocycloalkyl are spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, and spiro[2.5]octanyl (especially spiro[2.3]hexanyl and spiro[2.5]octanyl); such saturated bicyclic (Ce-sjspirocycloalkyl may be unsubstituted or substituted as explicitly defined. Examples of Cy 3 representing a saturated spiro bicyclic (C5-
  • Cy 3 is spiro[2.3]hexanyl, spiro[3.3]heptanyl, spiro[2.4]heptanyl, and spiro[2.5]octanyl; such Cy 3 may be unsubstituted or substituted as explicitly defined.
  • saturated fused or bridged bicyclic (C x-y )cycloalkyl (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated fused or bridged bicyclic hydrocarbon ring containing x to y carbon atoms.
  • R N3 representing a 5-membered saturated bridged bicyclic cycloalkyl is bicyclo[1.1.1]pentanyl.
  • R B3 representing a saturated bridged bicyclic (C6-8)cycloalkyl is bicyclo[2.2.1]heptanyl.
  • Cy 3 representing a saturated fused or bridged bicyclic (C5- 8)cycloalkyl are bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, and bicyclo[2.2.1]heptanyl; such Cy 3 may be unsubstituted or substituted as explicitly defined.
  • di-unsaturated bridged bicyclic (C x -y)cycloalkyl (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a mono-unsaturated bridged bicyclic hydrocarbon ring containing x to y carbon atoms (i.e., said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds).
  • R B3 representing a mono-unsaturated bridged bicyclic (C6-8)cycloalkyl is bicyclo[2.2.1 ]hept-2-en-2-yl.
  • heterocycle or “saturated monocyclic heterocycle”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups).
  • x- to y-membered heterocycle or "x- to y-membered saturated monocyclic heterocycle” refers to such a heterocycle containing x to y ring atoms. Such heterocycles are unsubstituted or substituted as explicitly defined.
  • NR N1 R N2 wherein R N1 and R N2 together with the nitrogen to which they are attached form a 5- to 7- membered saturated monocyclic heterocycle are pyrrolidinyl, piperidinyl, azepanyl, and morpholinyl; such 5- to 7- membered saturated monocyclic heterocycle may be unsubstituted or substituted as explicitly defined.
  • R N3 representing a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom
  • Cy 2 representing a 4- to 7-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from -0-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- are oxetanyl, tetrahydrofuranyl, tetrahydro-2/7-pyranyl, tetrahydro-2/7-thiopyran-1,1 -dioxide, 1-imino-1- oxidohexahydro-1 -A 6 -thiopyranyl, and 1 -methylimino-1-oxidohexahydro-1 -A 6 -thiopyranyl; such Cy 2 are substituted or unsubstituted as explicitly defined.
  • R 1 and R 2 together with the nitrogen to which they are attached, forming a 5- or 6-membered saturated monocyclic heterocycle (comprising said nitrogen atom, and zero or one additional ring heteroatom selected from 0 or S) are pyrrolidine, piperidine, thiazolidine, thiomorpholine, and morpholine; such 5- or 6-membered saturated monocyclic heterocycle may be unsubstituted or substituted as explicitly defined.
  • mono-unsaturated monocyclic heterocycle refers to a mono-unsaturated monocyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups), said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds.
  • x- to y-membered heterocycle or "x- to y-membered saturated monocyclic heterocycle” refers to such a heterocycle containing x to y ring atoms. Such heterocycles are unsubstituted or substituted as explicitly defined.
  • An example of Cy 2 representing a 4- to 7-membered mono-unsaturated monocyclic heterocycle comprising one ring heteroatomic group selected from -O-, -(SO2)-, -S(O)(NH)-, or -S(O)(NCH3)- is 3,6-dihydro-2/-/-pyranyl.
  • saturated spiro bicyclic heterocycle refers to a saturated spiro bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e. , such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups).
  • x- to y-membered saturated spiro bicyclic heterocycle refers to such a heterocycle containing x to y ring atoms.
  • R 2 representing a 7-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom is 2-oxaspiro[3.3]heptanyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, forming a 7- to 11 -membered saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms, are 2-azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan-6-yl, 2- oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan-2-yl, 1-oxa-6- azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8-azaspiro[5.5]unde
  • saturated fused bicyclic heterocycle used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated fused bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups).
  • x- to y-membered saturated fused bicyclic heterocycle refers to such a heterocycle containing x to y ring atoms.
  • R 1 and R 2 together with the nitrogen to which they are attached, forming an 8- to 10-membered saturated fused bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atom, are hexahydrocyclopenta[c]pyrrol-2(1 H)-yl, octahydroqui nol in- 1 (2H)-yl, and hexahydrofuro[3,2-c]py ridi n-5(4H)-yl .
  • fused bicyclic heterocycle used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a fused bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups), and wherein said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds.
  • x- to y-membered mono-unsaturated fused bicyclic heterocycle refers to such a heterocycle containing x to y ring atoms.
  • saturated bridged bicyclic heterocycle used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated bridged bicyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups).
  • x- to y-membered saturated bridged bicyclic heterocycle refers to such a heterocycle containing x to y ring atoms.
  • R 2 representing a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom is 7-oxabicyclo[2.2.1]heptanyl.
  • NR N1 R N2 wherein R N1 and R N2 together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom (and zero or one additional ring oxygen atom) are 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1 heptan-7-yl, 2-oxa- 5-azabicyclo[2.2.2]octan-5-yl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.
  • Examples of 7- to 9-membered saturated bridged bicyclic heterocycles formed by R 1 and R 2 together with the nitrogen to which they are attached are 7-azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, and 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; such 7- to 9-membered saturated bridged bicyclic heterocycle may be unsubstituted or substituted as explicitly defined.
  • saturated bridged tricyclic heterocycle refers to a saturated bridged tricyclic hydrocarbon ring comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or SO2; wherein it is understood that in each instance, the number and nature of ring heteroatoms or heteroatomic groups are as explicitly defined or may be defined more narrowly (i.e., such ring contains I comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups).
  • x- to y-membered saturated bridged tricyclic heterocycle refers to such a heterocycle containing x to y ring atoms.
  • R 1 and R 2 together with the nitrogen to which they are attached, forming a 10-membered saturated bridged tricyclic heterocycle comprising said nitrogen atom, and zero or one additional ring 0 atoms, are 2- azaadamantan-2-yl and 2-oxa-6-azaadamantan-6-yl.
  • x- to y-membered heterocycloalkan-diyl or "x- to y-membered saturated monocyclic heterocycloalkan- diyl” (x and y each being an integer), used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a bivalently bound heterocycloalkyl as defined before; wherein in each instance, the number and nature of ring heteroatoms or heteroatomic groups are explicitly defined.
  • Ring A represents a 4- to 7-membered saturated monocyclic heterocycloalkan-diyl comprising X 4 and zero or one further ring heteroatoms selected from 0 or S
  • the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X 4 and on the carbon atom attached to the group -CO-N(R 1 )(R 2 );
  • examples of such Ring A are azetidin-diyl, pyrrolidin-diyl, azepan-diyl, thiazolidin-diyl, and oxazolidin-diyl; such Ring A is unsubstituted, or substituted as explicitly defined.
  • the carbon atom of Ring A attached to the group -CO-N(R 1 )(R 2 ) is not further substituted.
  • x- to y-membered mono-unsaturated monocyclic heterocycloalkan-diyl refers to a bivalently bound monocyclic hydrocarbon ring containing x to y ring atoms of which one or two (especially one) ring atoms are heteroatoms independently selected from N, 0, or S, and wherein said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds.
  • Ring A represents a 4- to 6- membered mono-unsaturated monocyclic heterocycloalkan-diyl comprising X 4 and zero or one further ring N atom, and no further ring heteroatoms
  • the points of attachment of said mono-unsaturated heterocycloalkan-diyl in Formula (I) are on X 4 and on the carbon atom attached to the group -CO-N(R 1 )(R 2 ); the unsaturated (double) bond of said mono-unsaturated heterocycloalkan-diyl does not contain X 4 .
  • Ring A examples include 2, 5-dihy d ro- 1 H- pyrrol-1 ,2-diyl, 2,3-dihydro-1 H-pyrrol-1 ,5-diyl, 3,6-dihydropyridin-1 (2H)-1 ,2-diyl, and 4,5-dihydro-1 H-pyrazol-1,5- diyl); such Ring A may be unsubstituted or substituted as explicitly defined. In a particular embodiment, the carbon atom of Ring A attached to the group -CO-N(R 1 )(R 2 ) is not further substituted.
  • x- to y-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl refers to a bivalently bound saturated spiro, fused or bridged bicyclic hydrocarbon ring containing x to y ring atoms of which one or two (especially one) ring atoms are heteroatoms independently selected from N, 0, or S.
  • Ring A represents a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X 4 , and zero or one ring oxygen atom
  • the points of attachment of said bicyclic heterocycloalkan-diyl in Formula (I) are on X 4 and on the carbon atom attached to the group -C0-N(R 1 )(R 2 ).
  • Ring A examples include hexahydrocyclopenta[b]pyrrol-1 (2/-/),2-diyl, hexahydro-4H-furo[3,2-b]pyrrol-4,5-diyl, 2-azabicyclo[2.1.1]hexan-1 ,2- diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3-azabicyclo[3.1.0]hexan-2,3-diyl, 2-azabicyclo[2.2.1]heptan-1 ,2-diyl, 5- azaspiro[2.4]heptan-4,5-diyl, 5-azaspiro[2.4]heptan-5,6-diyl, and 6-azaspiro[2.5]octan-5,6-diyl); such Ring A is unsubstituted, or substituted as explicitly defined.
  • aryl used alone or in combination, means phenyl or naphthyl, especially phenyl.
  • R B3 represents phenyl
  • such phenyl may be unsubstituted or substituted as explicitly defined.
  • R B3 represents a mono-, di- or tri-substituted (especially mono- or di-substituted) phenyl, especially at least one of the substituent(s) is attached in para position with regard to the point of attachment of the rest of the molecule.
  • substituent(s) in para position is/are (Ci-3)alkyl (notably methyl), halogen (notably fluoro), or (Ci-3)alkoxy (especially methoxy).
  • 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, or 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
  • R B3 represents a 5- or 6- membered heteroaryl
  • such heteroaryl comprises one to three ring heteroatoms independently selected from N, 0, or S, wherein said heteroaryl is especially linked to the rest of the molecule via a ring carbon atom.
  • R B3 is notably isothiazolyl, oxazolyl, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl; such 5- or 6-membered heteroaryl may be unsubstituted or substituted as explicitly defined.
  • 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).
  • 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.
  • X 1 represents N or CR B2 , wherein R B2 represents hydrogen, halogen (especially fluoro), or (Ci-3)alkyl (especially methyl), and X 2 represents CH [in particular X 1 represents CH, C-CH3, or N, and X 2 represents CH],
  • Another embodiment relates to compounds according to embodiment 1), wherein X 1 represents CH and X 2 represents N.
  • R B1 represents (Ci-3)alkyl (especially methyl, ethyl, or isopropyl) or (Ci)fluoroalkyl (especially trifluoromethyl) [in particular R B1 represents methyl or trifluoromethyl].
  • R B3 represents: OR 01 , wherein R 01 represents (C ⁇ alkyl (especially propyl, isopropyl, sec-butyl, or isobutyl) that is substituted with zero, one or two (Ci)fluoroal ky I (especially difluoromethyl or trifluoromethyl); [notably OR 01 represents propoxy, isopropoxy, sec-butoxy, isobutoxy, (1,1-difluoropropan-2-yl)-oxy, (3,3-difluoro-2,2- dimethyl-propyl)-oxy, (1,1 , 1-trifluoropropan-2-yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1, 1 ,1 , 3,3,3— hexafl uoropropan-2-yl)-oxy; in particular OR 01 represents sec-butoxy]; or NR N1 R N
  • ⁇ R N1 represents:
  • ⁇ R N2 represents:
  • (C2-5)alkyl especially propyl, isopropyl, sec-butyl, or fert-butyl); wherein said (C2-5)alkyl is unsubstituted, or mono- or di-substituted (especially unsubstituted or monosubstituted); wherein the substituents are independently selected from the group consisting of: (Ci)fluoroalkyl (especially trifluoromethyl), (C ⁇ cycloalkyl (especially cyclopropyl), and (Ci-3)alkoxy (especially methoxy); or
  • NR N1 R N2 represents isopropyl-amino, sec-butyl-amino, terf-butyl-amino, (l-methyl-cyclopropyl)-amino, (l-cyclopropyl-ethyl)-amino, (1 -methoxy propan-2-yl)-ami no, (1, 1 ,1 -tr if I uoropropan-2-y l)-ami no, (1 , 1 ,1 -trifl uorobu tan-2 -y I )-am i no, (1 -cy clopropy I-2, 2, 2- trifluoroethyl)-amino, (isopropyl)-(methyl)-amino, (ferf-butyl)-(methyl)-amino, (cyclopropyl)- (methyl)-amino, diethyl-amino, (ethyl)-(isopropyl-
  • R N1 and R N2 together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl), (Ci.
  • R N2 represents pyrrolidin-1 -yl, piperidin-1 - yl, 2-methylpyrrolidin-1-yl, 2-(trifluoromethyl)pyrrolidin-1-yl, 2-methylpiperidin-1-yl, 3- fluoropiperidin-1-yl, 4-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2- (methoxymethyl)piperidin-l-yl, 2,5-dimethylpyrrolidin-1-yl, 2,3-dimethylpyrrolidin-1-yl, 2-ethyl-5- methylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1 -yl, azepan-1-yl, 3-methylmorpholin-4-y
  • R N1 and R N2 together with the nitrogen to which they are attached form a 7- to 8-membered saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom;
  • group NR N1 R N2 represents 2-azabicyclo[2.2.1]heptan-2-yl, 7- azabicyclo[2.2.1 heptan-7-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, or 3-oxa-8- azabicyclo[3.2.1]octan-8-yl)]; or a saturated or mono-unsaturated monocyclic (Cs-zjcycloalkyl (notably cyclopentyl, cyclopent-1 -en-1-yl, cyclohexyl, cyclohex-1 -en-1 -yl, cycloheptyl, or cyclohept-1-en-1-yl); wherein said (C4-6)cycloal
  • R B3 represents: propoxy, isopropoxy, sec-butoxy, isobutoxy, (1 ,1-difluoropropan-2-yl)-oxy, (3,3-difluoro-2,2-dimethyl- propyl)-oxy, (1 ,1 ,1-trifluoropropan-2-yl)-oxy, (4,4,4-trifluorobutan-2-yl)-oxy, or (1 , 1 ,1 , 3,3,3- hexafluoropropan-2-yl)-oxy [in particular R B3 represents sec-butoxy]; or NR N1 R N2 , wherein independently:
  • ⁇ R N1 represents:
  • ⁇ R N2 represents:
  • R N1 and R N2 together with the nitrogen to which they are attached form a 5- to 7-membered saturated monocyclic heterocycle comprising said nitrogen atom, and zero or one additional ring oxygen atom (especially pyrrolidinyl, piperidinyl, azepanyl, or morpholinyl); wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and (Ci.
  • NR N1 R N2 represents piperidin-1-yl, 2-methylpiperidin-1-yl, 2-(trifluoromethyl)piperidin-1-yl, 2,5- dimethylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1-yl, azepan-1-yl, or 3,5-dimethylmorpholin-4-yl]; or a saturated monocyclic (C4-e)cycloalkyl (notably cyclohexyl); wherein said saturated (C4-6)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently (Ci-s)al ky I (especially methyl); or a mono-unsaturated monocyclic (Ce-zjcycloalkyl (notably cyclohex-1 -en-1-yl, or cyclohept-1
  • R B3 represents: NR N1 R N2 , wherein independently:
  • ⁇ R N1 represents (Ci-3)alkyl (especially methyl, ethyl, or isopropyl);
  • ⁇ R N2 represents (C ⁇ alkyl (especially isopropyl);
  • NR N1 R N2 represents (ethyl)-(isopropyl)-amino, diisopropyl-amino, or (isopropyl)-(methyl)-amino]; or
  • R N1 and R N2 together with the nitrogen to which they are attached form a heterocycle selected from pyrrolidinyl, piperidinyl, or morpholinyl; wherein said heterocycle is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)alkyl (especially methyl) and (Ci-2)fluoroalkyl (especially trifluoromethyl or 2,2,2- trifluoroethyl); [in particular such group NR N1 R N2 represents piperidin-1-yl, 2-methylpiperidin-1 -yl, 2-(trifluoromethyl)piperidin-1 -yl, 2,5-dimethylpyrrolidin-1-yl, 2,6-dimethylpiperidin-1-yl, or 3,5- dimethylmorpholin-4-yl]; or a mono-unsaturated monocyclic (C6-z)cycloalkyl (notably cyclohex- 1-
  • Ring B represents 2- isopropoxy-6-methylpyridin-3-yl, 6-methyl-2-propoxypyridin-3-yl, 2-(sec-butoxy)-6-methylpiridin-3-yl, 2-isobutoxy- 6-methylpyridin-3-yl, 2-((1,1-difluoropropan-2-yl)oxy)-4-methylphenyl, 2-(3,3-difluoro-2,2-dimethyl-propoxy)-4- methy I phenyl , 4-methy l-2-((1 , 1 ,1 -trifl uoropropan-2-yl)oxy) phenyl , 6-methy l-2-(1 ,1 , 1 -trifl uoropropan-2- yl)oxy)pyridin-3-yl, 4-methyl-2-((4,4,4-trifluorobutan-2-yl)oxy)phenyl, 2-(((4,4,4-trifluorobutan-2-y
  • Ring B represents 2-(sec- butoxy)-6-methylpiridin-3-yl, 2-(isopropylamino)-6-methylpyridin-3-yl, 2-(fert-butylamino)-6-methylpyridin-3-yl, 2- (isopropyl(methyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl, 2- (ethyl(isopropyl)amino)-6-(trifluoromethyl)pyridin-3-yl, 2-(ethyl(isopropyl)amino)-4-methylphenyl, 2- (diisopropylamino)-6-methylpyridin-3-yl, 4-methyl-2-(piperidin-1-yl)phenyl, 6-methyl-2-(piperidin-1-yl)pyridin-3-yl, 4-methyl-2-(piperidin-1-yl)phenyl, 6-
  • Ring B represents 2- (isopropyl(methyl)amino)-6-methylpyridin-3-yl, 2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl, 2- (ethyl(isopropyl)amino)-6-(trifluoromethyl)pyridin-3-yl, 2-(ethyl(isopropyl)amino)-4-methylphenyl, 2- (diisopropylamino)-6-methylpyridin-3-yl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)phenyl, 4-methyl-2-(piperidin-1-yl)pheny
  • Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein X 3 represents 0.
  • X 3 represents NR N3 , wherein R N3 represents hydrogen, (Ci-3)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom (especially oxetanyl or tetrahydrofuranyl), a 5-membered saturated bridged bicyclic cycloalkyl (especially bicyclo[1.1.1]pentanyl), phenyl, or pyridinyl.
  • R N3 represents hydrogen, (Ci-3)alkyl (especially methyl or ethyl), (C3-6)cycloalkyl (especially cyclopropyl), a 4- or 5-membered saturated monocyclic heterocycle comprising one ring oxygen atom (especially oxetanyl or tetrahydrofuranyl), a 5-membered saturated bridged bicyclic cycloalkyl (especially bicyclo[1.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein X 3 represents NR N3 , wherein R N3 represents hydrogen, (Ci-3)alkyl (especially methyl), or (C3-6)cycloalkyl (especially cyclopropyl).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X 4 represents N and Ring A represents:
  • Ring A represents 2,5-dihydro-1 H-pyrrol-1 ,2-diyl or 3-methyl-4,5-dihydro-1 H-pyrazol-1 ,5-diyl];
  • a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X 4 , and zero or one ring oxygen atom (notably hexahydrocyclopenta[b]pyrrol-1 (2/7),2-diy I, hexahydro-4/-/- furo[3,2-b]pyrrol-4,5-diyl, azabicyclo[2.1.1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, or azaspiro[2.4]heptan-diyl; in particular azabi cyclo [2.1 .1]hexan-diyl, azabicyclo[3.1.0]hexan-diyl, azabicyclo[2.2.1]heptan-diyl, azaspiro[2.4]heptan-diyl,
  • Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X 4 represents N and Ring A represents:
  • Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X 4 represents N and Ring A represents hexahydrocyclopenta[b]pyrrol-1 (2/-/),2-diyl, hexahydro-4/-/-furo[3,2-b]pyrrol- 4,5-diyl, 4-methyl-2-azabicyclo[2.1 ,1]hexan-1 ,2-diyl, 2-azabicyclo[3.1.0]hexan-2,3-diyl, 3-azabicyclo[3.1.0]hexan- 2,3-diyl, 2-azabicyclo[2.2.1]heptan-1,2-diyl, 5-azaspiro[2.4]heptan-4,5-diyl, 5-azaspiro[2.4]heptan-5,6-diyl, 1,1- difluoro-5-azaspiro[2.4]heptan-5,6-diyl, or 6-azaspiro[2.5]octan-5
  • FIG. 16 Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X 4 represents N and Ring A represents 4-methyl-2-azabicyclo[2.1 .1]hexan-1 ,2-diyl, 2-azabicyclo[3.1 .0] hexan-2, 3-diy I , 3-azabicyclo[3.1.0]hexan-2,3-diyl, 2-azabicyclo[2.2.1]heptan-1 ,2-diyl, or 5-azaspiro[2.4]heptane-4,5-diyl, 5- azaspiro[2.4]heptan-5,6-diyl [notably 4-methyl-2-azabicyclo[2.1.1]hexan-1,2-diyl, 3-azabicyclo[3.1.0]hexan-2,3- diyl, or 2-azabicyclo[2.2.1]heptan-1 ,2-diyl],
  • Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X 4 represents CH and Ring A represents a monocyclic (Cs-ejcycloalkan-diyl .
  • a compound of Formula (I) represents either a compound of Formula (II), or a compound of Formula (III), or any mixture thereof (especially enantiomerically-enriched compound of Formula (II)):
  • R 1 represents hydrogen; methyl or ethyl.
  • R 2 represents: -(CH2) q -Cy 1 ; wherein q is 0 or 1 (especially 0) and Cy 1 represents a saturated monocyclic (CsjJcycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl or isopropyl), (Ci-3)alkoxy (especially methoxy), cyano, and hydroxy; [notably such R 2 represents (cyclopropyl)methyl, 2- iso
  • R 2 represents 2- isopropylcyclopropyl, 3-(trifluoromethyl)cyclobutyl, 3-(difluoromethyl)cyclobutyl, 3,3-dimethylcyclobutyl, 3,3-difluorocyclobutyl, (3,3-difluorocyclobutyl)methyl, (cyclopentyl)methyl, 2-methoxycyclopentyl, 2- cyanocyclopentyl, 3-fluorocyclopentyl, 3-cyanocyclopentyl, 3-cyanocyclopentyl, 3,3-dimethylcyclopentyl, 3,3- difluorocyclopentyl, cyclohex
  • R 2 represents: -(CH2) q -Cy 1 ; wherein q is 0 or 1 (especially 0) and Cy 1 represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (C3-z)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-3)fluoroalkyl (especially difluoromethyl or trifluoromethyl), halogen (especially fluoro), (Ci-3)alkyl (especially methyl or isopropyl), (Ci-3)alkoxy (especially methoxy), cyano, and hydroxy; [notably such R 2 represents 2-isopropylcyclopropyl,
  • R 2 represents: -(CH2) q -Cy 1 ; wherein q is 0 and Cy 1 represents a saturated monocyclic (C3-z)cycloalkyl; wherein said monocyclic (Cs-zjcycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (especially fluoro), (Ci-s)alkyl (especially methyl), (Ci-3)alkoxy (especially methoxy), and cyano; [notably such R 2 represents 3,3-dimethylcyclobutyl,
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein R 1 and R 2 together with the nitrogen to which they are attached form:
  • a 7- to 11-membered (especially 8-membered) saturated spiro bicyclic heterocycle comprising said nitrogen atom, and zero, one or two additional ring 0 atoms (notably said heterocycle is 2- azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.4]octan-2-yl, 6-azaspiro[2.5]octan- 6-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 6-oxa-2-azaspiro[3.5]nonan- 2-yl, 1-oxa-6-azaspiro[3.5]nonan-6-yl, 1-oxa-7-azaspiro[3.5]nonan-7-yl, 2-oxa-8- azaspiro[5.5]undecan-8-yl, 3-ox
  • a 7- to 9-membered (especially 7- to 8-membered) saturated bridged bicyclic heterocycle comprising said nitrogen atom, and zero additional ring heteroatoms, or one or two additional ring 0 atoms, or one additional ring S atom
  • said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3- oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, or 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl; in particular said 7- to 9-membered bridged heterocycle is 7- azabicyclo[2.2.1]heptan-7-yl or 8
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein R 1 and R 2 together with the nitrogen to which they are attached form:
  • an 8-membered saturated spiro bicyclic heterocycle comprising said nitrogen atom (notably said heterocycle is 6-azaspiro[2.5]octan-6-yl); or
  • R 1 and R 2 together with the nitrogen to which they are attached represent: (4,4-difluorocyclohexyl)-(methyl)-amino, (4,4- difluorocyclohexyl)-amino, (3-cyanocyclopentyl)-amino, (1,1-difluorospiro[2.5]octan-6-yl)-(methyl)-amino, (1 ,1- difluorospiro[2.5]octan-6-yl)-amino, (3-fluorocyclopentyl)-amino, (bicyclo[4.1.0]heptan-3-yl)-amino,
  • Another embodiment relates to compounds according to embodiment 1) which are selected from the following compounds:
  • (2S)-N-((3R,6s)-1 1-Difluorospiro[2.5]octan-6-yl)-N-(methyl)- ⁇ 1- ⁇ (R)-N-(methyl)-(2-cyclohexyl-6-methyl-pyridin-3- yl)-sulfonimidoyl ⁇ -pyrrolidine ⁇ -2-carboxamide;
  • the compounds of Formula (I) according to embodiments 1) to 27) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral e.g. in form of a tablet or a capsule) 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 I prophylaxis 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 embodiments 1) to 27).
  • compounds are described as useful for the prevention I prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention I prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention I 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 of Formula (I) according to any one of embodiments 1 ) to 27) are useful for the prevention I prophylaxis or treatment of diseases or disorders relating to the OX2R receptor, and notably in disease and disorders in which agonism of OX2R plays a role.
  • Disease and disorders in which agonism of OX2R plays a role are particularly disease and disorders associated with difficulties maintaining wakefulness.
  • Subjects presenting disease and disorders associated with difficulties maintaining wakefulness complain of: feelings of excessive sleepiness; episodes of inadvertently falling asleep, including sleep attacks (episodes of falling asleep without prodromal symptoms of drowsiness); a prolonged main sleep episode that is unrefreshing; recurrent naps in the same day; or sleep inertia (prolonged difficulty waking up, with irritability, automatic behavior or confusion).
  • the compounds of Formula (I) according to embodiments 1) to 27) are useful for improving wakefulness in a subject (especially in a subject having hypersomnia or narcolepsy, or presenting excessive daytime sleepiness (EDS)).
  • the term "improving wakefulness in a subject” refers to improving symptoms of, or to the prevention I prophylaxis or treatment of: hypersomnia, particularly prevention I prophylaxis or treatment of:
  • narcolepsy including especially narcolepsy type 1 and narcolepsy type 2;
  • secondary narcolepsy associated with inherited disorders such as Prader-Willi syndrome, Niemann- Pick C disease, or myotonic dystrophy
  • EDS excessive daytime sleepiness
  • said medical disorder is especially an objective sleep disturbance, obesity, diabetes, a neurodegenerative disorder, an auto-immune disorder, a psychiatric disorder, or insufficient sleep syndrome; in particular:
  • ⁇ improving symptoms of EDS associated with a neurodegenerative disorder notably associated with: Alzheimer's, Parkinson's, Lewy body dementia, Perry syndrome, multiple system atrophy, or Huntington's disease;
  • narcolepsy ⁇ improving symptoms pronounced of narcolepsy in subjects having an auto-immune disorder (especially neuromyelitis optica, multiple sclerosis, Guillain-Barre syndrome, or anti-Ma2 encephalitis);
  • neuropsy type 1 describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions).
  • Fatigue is characterized by a lack of energy ("an overwhelming sense of tiredness, a feeling of exhaustion").
  • neuropsychiatric disorders notably mood disorders, particularly depression (such as major depressive disorder (MDD)); • pain, particularly inflammatory pain, or chronic neuropathic pain;
  • mood disorders particularly depression (such as major depressive disorder (MDD)
  • pain particularly inflammatory pain, or chronic neuropathic pain
  • agonism of OX2R plays a role in:
  • the term “subject” refers to a mammal, especially a human; in the context of a certain diagnosis or disease, the term “subject” and “patient” are to be understood as being interchangeable.
  • the compounds of Formula (I) according to any one of embodiments 1) to 27) are in particular useful as therapeutic agents for the prevention I prophylaxis or treatment of a disease and disorders associated with difficulties maintaining wakefulness. They can be used as single therapeutic agents or in combination with one or more additional therapeutic agents.
  • therapeutic agents include modafinil, pitolisant, sodium oxybate, solriamfetol, armodafinil, dextroamphetamine, methylphenidate, clarithromycin, venlafaxine, clomipramine and lithium (see for example Mask! K. et al. J Clin Sleep Med. 2021 , 17(9), 1881-1893; Bassett! C. et al. Eur J Neurol. 2021 , 00, 1-16).
  • the invention thus, also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and one or more additional therapeutic agents.
  • the invention thus, further relates to a kit comprising a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).
  • a kit comprising a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).
  • a kit comprising a pharmaceutical composition, said composition comprising a pharmaceutically acceptable carrier material, and: a compound of Formula (I) according to any one of embodiments 1) to 27); and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).
  • EDS daytime sleepiness
  • any preferences and (sub-)embodiments indicated for the compounds of Formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, or uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of Formula (II), Formula (III) and Formula (IV).
  • 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) including metabolic stability potentially affecting (human) bioavailability and/or dosage requirements, 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
  • a further aspect of the invention is a process for the preparation of compounds of Formula (I).
  • Compounds according to Formula (I) of the present invention can be prepared from commercially available or well known starting materials according to the methods described in the experimental part, by analogous methods, or according to the general sequence of reactions outlined below, wherein R 1 , R 2 , R B1 , R B3 , X 1 , X 2 , X 3 , X 4 , Ring A, and Ring B are as defined for Formula (I).
  • R 1 , R 2 , R B1 , R B3 , X 1 , X 2 , X 3 , X 4 , Ring A, and Ring B are as defined for Formula (I).
  • Other abbreviations used herein are explicitly defined, or are as defined in the experimental section.
  • the generic groups R 1 , R 2 , R B1 , R B3 , X 1 , X 2 , X 3 and X 4 might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG).
  • 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.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse.
  • Amines 3 are either commercially available, prepared following procedures described in the literature, or prepared as described in the experimental part.
  • Compound 4 can be deprotected using standard deprotection methods known in the literature and familiar to the person skilled in the art to give 5 (or the corresponding salt, like HCI or TFA salts).
  • Amine 5 is condensed with a sulfonyl chloride 6 (where Hal is a halogen such as I, Br, Cl, or F) in solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA to give 7.
  • amine 5 can also be condensed with a sulfonyl chloride of general formula 10 in solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA to give 9.
  • Sulfonyl chlorides 6 and 10 and amines 3 may be commercially available, prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.
  • Scheme 1 Synthesis of sulfonamide compound 9 by variation of sulfonamide part in the last step.
  • variation in the amide functional group can be introduced at the very last step following the procedures described in Scheme 2.
  • An appropriate aminoester 11 (or the corresponding salt, like HCI or TFA salts) can be reacted with sulfonyl chloride 6 (where Hal is a halogen such as I, Br, Cl, or F) in solvent such as DCM, DMF, MeCN, and in presence of a base such as TEA or DIPEA to yield intermediate 12.
  • sulfonyl chloride 6 where Hal is a halogen such as I, Br, Cl, or F
  • solvent such as DCM, DMF, MeCN
  • a base such as TEA or DIPEA
  • Intermediate 13 can also be synthesized starting from aminoester 11 (or the corresponding salt, like HCI or TFA salts) by condensation with a sulfonyl chloride 10 comprising R B3 .
  • Ester 13 can then be hydrolysed into the corresponding acid (14) using a base such as LiOH or NaOH in a mixture of solvents such as THF/water.
  • Amide formation between carboxylic acid 14 and amine 3 in a solvent such as THF, DMF, DCM or MeCN in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC or similar and a base such as DIPEA, TEA or N-methylmorpholine yields compound with formula 9.
  • Scheme 2 Synthesis of sulfonamide 9 by variation of the amide substituent in the last step.
  • Step I Sulfonamide formation, ii) Cross-coupling, ill) Hydrolysis, iv) Amide formation, v) Hydrolysis vi) SNAP reaction.
  • An arylthiol (16) can be oxidized into its corresponding sulfinate ester 17 by reaction with NBS and MeOH in a solvent such as DCM.
  • Sulfinate ester 17 can be converted into sulfinamide with general structure 19 by reaction with primary amine 18 (or the corresponding salt, like HCI or TFA salts) using a base such as n-BuLi in a solvent like THF.
  • Compound 19 can then be condensed with 5 in presence of a chlorinating agent such as fert-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2- dichloroethane to give SIA derivative 20.
  • a chlorinating agent such as fert-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2- dichloroethane to give SIA derivative 20.
  • arylthiols 16 are prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.
  • Sulfinate ester 17 can be converted into sulfinamide 21 by reaction with lithium hexamethyldisilazide (LHMDS) in a solvent like THF and hydrolysis with sat. aq. NH4CI.
  • Intermediate 21 can be protected with an appropriate protecting group (PG) to yield 22 using standard protection methods known in the literature and familiar to the person skilled in the art.
  • Compound 22 can be condensed with 5 in presence of a chlorinating agent such as ferf-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2-dichloroethane to give SIA intermediate 23.
  • Compound 24 can then be produced by subjecting intermediate 23 to standard deprotection methods known in the literature and familiar to the person skilled in the art.
  • 20 and 24 can be obtained via a late-stage R B3 functionalization as described in Scheme 5.
  • An arylthiol (25) can be oxidised into its corresponding sulfinate ester (26) and converted into sulfinamide 27 in a similar way as described herein before for the preparation of intermediates 17 and 21.
  • Sulfinamide 28 can be protected with an appropriate protecting group (PG) to yield 28 using standard protection methods known in the literature and familiar to the person skilled in the art.
  • SIA 29 can be obtained by reacting intermediate 28 with 5 in presence of a chlorinating agent such as ferf-butyl hypochlorite or N-chlorosuccinimide in a solvent such as DCM or 1 ,2- dichloroethane.
  • the PG can be cleaved using standard deprotection methods known in the literature and familiar to the person skilled in the art to yield 24.
  • SIA 20 can be obtained by subjecting 24 to alkylation using a base such as NaH or KOfBu and an alkylating agent such as an alkyl halide, or an alkyl sulfonates, in a solvent such as DMF.
  • arylthiols 25 can be prepared following the procedures described in the literature, a method analogous thereto, or as described in the experimental part herein below.
  • Intermediate 32 is subjected to a Suzuki-Miyaura cross-coupling reaction with the appropriate arylboronic acid or ester in a solvent such as THF or DME and in presence of a base such as K2CO3, NaHCOa or K3PO4 and a Pd catalyst such as Pd (PPhs)4 to give 33.
  • Thioether 33 can be oxidized in presence of an oxidant such as MCPBA and in a solvent such as DOM to lead to sulfone 34.
  • Derivative 34 can be hydrolysed using standard methods as described herein before into its corresponding carboxylic acid 35 with frans-relative configuration.
  • 36 can be produced by a R B3 late-stage functionalization as described in the sequence in Scheme 7.
  • an oxidant such as MCPBA and in a solvent such as DCM.
  • Hydrolysis of the ester using a base such as LiOH or NaOH in a mixture of solvents such as THF/Water gives carboxylic acid 38 with frans-relative stereochemistry.
  • Amide 40 can be subjected to hydrosulfonylation in presence of an iridium catalyst as tris(2-phenylpyridine)iridium and a radical reducing agent such as (TMS ⁇ SIH in a solvent such as MeCN and under blue LED irradiation (Angew.Chem.lnt.Ed. 2020,59,11620-11626).
  • an iridium catalyst as tris(2-phenylpyridine)iridium and a radical reducing agent such as (TMS ⁇ SIH in a solvent such as MeCN and under blue LED irradiation (Angew.Chem.lnt.Ed. 2020,59,11620-11626).
  • Intermediate 43 can be oxidised into 44 using an oxidant such as MCPBA and in a solvent such as DCM.
  • Carboxylic acid 44 can be activated using a coupling reagent such as TBTU, HBTU, HATU, EDC, pyCloP (or similar) and be subjected to amide coupling with amine 3 (or the corresponding salt, like HCI or TFA salts) in presence of a base such as DIPEA, TEA, or N-methylmorpholine, in a solvent such as THF, DMF, DCM or MeCN, to give 39.
  • a coupling reagent such as TBTU, HBTU, HATU, EDC, pyCloP (or similar) and be subjected to amide coupling with amine 3 (or the corresponding salt, like HCI or TFA salts) in presence of a base such as DIPEA, TEA, or N-methylmorpholine, in a solvent such as THF, DMF, DCM or MeCN, to give 39.
  • a coupling reagent such as TBTU, HBTU,
  • Scheme 7 Synthesis of sulfone compound 36 by late-stage R B3 functionalization.
  • Step I Oxidation, ii) Hydrolysis, ill) Amide coupling, iv) Cross-coupling/SNAr, v) Amide coupling, vi) Hydrosulfonylation, vii) Cross-coupling, viii) Oxidation, ix) Amide coupling.
  • LC-MS-conditions Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD, DAD: Acquity UPLC PDA Detector.
  • Method Gradient: 2 % B to 98 % B over 2.0 min. Flow: 1.0 mL/min. Detection at 214 nm and MS, retention time IR is given in min.
  • LC-MS- conditions Analytical UPLC on a Agilent Zorbax RRHD SB-Aq (2.1x50 mm, 1.8 .m); detection at 210 nM and MS; UPLC/MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; Gradient of water/ 0.04% TFA (A) and MeCN (B). The eluent flow rate was 0.8 mL/min and the characteristics of the eluting mixture proportion in function of the time t from start of the elution are summarized in the table below (a linear gradient being used between two consecutive time points):
  • Preparative HPLC/MS purifications are performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Finnigan AQA MS detector system, and a Dionex UV detector, using a Waters Xbridge C18 or a Waters Atlantis column, with a linear gradient of water/formic acid 0.02% (A) and MeCN (B) (acidic prep. HPLC ), or water/ammonia 0.02% (A) and MeCN (B) (basic prep. HPLC ).
  • Preparative chiral SFC 1 A Chiralpak AY-H column (30 x 250 mm, 5 m) was used. The modifier was EtOH (10%), run for 10 min and at a flow rate of 160 mL/min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C.
  • Preparative chiral SFC 2 A ChiralPak IG column (30 x 250 mm, 5 pm) was used. The modifier was MeOH (20%) with EtaNH (0.1 %), run for 3:80 min and at a flow rate of 160 mL/min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C
  • Preparative chiral SFC 4 A ChiralPak IB column (30 x 250 mm, 5 pm) was used. The modifier was MeOH (10%), run for 5 min and at a flow rate of 160 mL/min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C
  • Preparative chiral SFC 5 A ChiralPak IC column (30 x 250 mm, 5 pm) was used. The modifier was CHaCN/EtOH 1 :1 (25%), run for 7 min and at a flow rate of 160 mL/min. The following system settings were used: backpressure 100 bar, temperature pumphead 5 °C, temperature fraction module 20 °C, and temperature column department 40 °C. FC
  • Flash Chromatographies were performed using an automated system, typically combiflash from Teledyne ISCO.
  • Phase separator cartriges used were Isolute® purchased from Biotage
  • tert-butyl (4,4-difluorocyclohexyl)carbamate (6.23 g, 26.5 mmol, 1 eq) in DMF (50 mL) was added dropwise and the reaction mixture was stirred at 0 °C for 1 h.
  • Methyl iodide (3.30 mL, 52.9 mmol, 2 eq) was added and the reaction mixture was stirred at 0 °C for 3 h.
  • Water (400 mL) was slowly added at 0 °C and the reaction mixture was extracted twice with EtOAc. The combined org.
  • Example 1.3 (S)-1-(5,2'-Dimethyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and 2-tolylboronic acid in analogy to Example 1.1 to give the title compound.
  • LC-MS (1): t R 1.317 min; [M+H] + : 491.2.
  • Example 1.4 to Example 1.5 were synthesized using 4,4-difluoro-N-methylcyclohexan-1-amine hydrochloride, L- proline, the appropriate phenyboronic acid, and following the procedure described in Example 1.1.
  • LC-MS data of Example 1.4 to Example 1.5 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Methyl ((2'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)sulfonyl)-L-prolinate methyl ((2-bromo-4- methylphenyl)sulfonyl)-L-prolinate (9.97 g, 27.5 mmol, 1 eq), (2-fluorophenyl)boranediol (6.08 g, 41.3 mmol, 1.5 eq), Na2CC>3 (8.79 g, 82.5 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (2.25 g, 2.75 mmol, 0.1 eq) were dissolved in degassed 1,4-dioxane I water 4:1 (1.0 mL) and the resulting mixture was stirred at 70 °C for 2.5 h.
  • Example 1.8 to Example 1.10 were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and the appropriate phenylboronic acid in analogy to Example 1.1.
  • LC-MS data of Example 1.8 to Example 1.10 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.12 to Example 1.16 were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and the appropriate phenylboronic acid in analogy to Example 1.11.
  • LC-MS data of Example 1.12 to Example 1.16 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.18 (S)-1-(2-Cyclohexyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclohex-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound.
  • LC-MS (1): t R 1.390 min; [M+H] + : 483.2.
  • Example 1.20 (S)-1-(2-Cyclopentyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclopent-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound.
  • LC-MS (1): IR 1.33 min; [M+H] + : 469.2.
  • Example 1.22 (S)-1-(2-Cycloheptyl-4-methyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(2-cyclohept-1-enyl-4-methyl-benzenesulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide in analogy to Example 1.17 to give the title compound.
  • LC-MS (1): t R 1.444 min; [M+H] + : 497.4.
  • Example 1.23 to Example 1.24 were synthesized using (S)-N-(4,4-difluorocyclohexyl)-1-((2-fluoro-4- methylphenyl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and the appropriate amine or amine salt in analogy to Example 1.21.
  • LC-MS data of Example 1.23 to Example 1.24 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.26 to Example 1.30 were synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and the appropriate aryl halide in analogy to Example 1.25.
  • LC-MS data of Example 1.26 to Example 1.30 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.32 to Example 1.37 were synthesized according to the procedures described herein before using (S)- N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide hydrochloride, the appropriate sulfonyl chloride and the appropriate boronic acid or boronic ester.
  • LC-MS data of Example 1.32 to Example 1.37 are listed in the table below.
  • Example 1.38 (S)-1-(4-Methyl-2-pyrimidin-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2- (4, 4, 5, 5-tetramethy I- 1 ,3, 2-d ioxaborol an -2-y l)pheny I )sulfony l)py rrol id i ne-2-carboxamide and 2-bromopyrimidine in analogy to Example 1.25 to give the title compound.
  • LC-MS (1): IR 0.957 min; [M+H] + : 479.3.
  • Example 1.39 (S)-1-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-amide: was synthesized using ((2'-fluoro-5-methyl-[1,T-biphenyl]-2-yl)sulfonyl)-L-proline and 4,4- difluorocyclohexan- 1 -amine in analogy to Example 1 .7 to give the title compound.
  • LC-MS (1): IR 1 .204 min; [M+H] + : 481.2.
  • Example 1.40 (S)-1-(5-Chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide hydrochloride, 2-bromo-4-chlorobenzene-1 -sulfonyl chloride, and 2-fluorophenylboronic acid in analogy to Example 1.31 to give the title compound.
  • LC-MS (1): IR 1.291 min; [M+H] + : 515.1.
  • Example 1.41 to Example 1.49 were synthesized according to the procedures described herein before using ((2- fluoro-5-methyl-[1, -biphenyl]-2-yl)sulfonyl)-L-proline and the appropriate amine or amine salt.
  • Example 1.41 to Example 1.49 are listed in the table below.
  • the LC-MS conditions used were LC-MS (1).
  • Example 1.52 (2S)-1-((2',6-difluoro-[1,r-biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N- methylpyrrolidine-2-carboxamide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2- carboxamide hydrochloride, 2-bromo-3-fluorobenzenesulfonyl chloride, and 2-fluorophenylboronic acid in analogy to Example 1.31 to give the title compound as a mixture of 2 atropisomers.
  • Example 1.53 to Example 1.60 were synthesized according to the procedures described herein before using ((2 - fluoro-5-methyl-[1 ,1 '-biphenyl]-2-yl)sulfonyl)-L-proline and the appropriate amine or amine salt.
  • LC-MS data of Example 1.53 to Example 1.60 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.60 (S)-1-(5-Cyclopropyl-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: (S)-1-(5-chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide (20.0 mg, 0.0388 mmol, 1 eq) and SPhos Pd G2 (1.12 mg, 0.00155 mmol, 0.04 eq) were dissolved in THF (0.5 mL) under N2 atmosphere.
  • Example 1.61 (S)-1-(2'-Fluoro-5-isopropyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: was synthesized using (S)-1-(5-chloro-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide and 2-propylzinc bromide (0.5 M in THF) in analogy to Example 1.60 to give the title compound.
  • LC-MS (1): IR 1.344 min; [M+H] + : 523.3.
  • Example 1.62 (S)-4,4-Difluoro-1-(2'-fluoro-5-methyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: 2-Bromo-2'-fluoro-5-methyl-1 , 1 '-biphenyl : to a degassed soln, of 2-bromo-5-methylphenylboronic acid (443 mg, 2.00 mmol, 1 eq), 2-fluoroiodobenzene (0.233 mL, 2.00 mmol, 1 eq), and CsF (0.133 mL, 3.60 mmol, 1.8 eq) in dioxane (6 mL), PPh 3 (106 mg, 0.400 mmol, 0.2 eq) and Pd(OAc)2 (22.5 mg, 0.100 mmol, 0.05 eq) were added.
  • Example 1.64 to Example 1.65 were synthesized according to the procedures described herein before using (S)- N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)sulfony l)pyrrolidine-2-carboxamide and the appropriate aryl halide (chloride, bromide, or iodide).
  • LC-MS data of Example 1.64 to Example 1.65 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.68 to Example 1.83 were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1,1'- biphenyl]-2-sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to example 1.62.
  • LC-MS data of Example 1 .68 to Example 1 .83 are listed in the table below.
  • Example 1.84 (S)-1-(5-Ethyl-2'-fluoro-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4-difluoro- cyclohexyl)-N-methyl-amide: (S)-1-(2'-fluoro-5-vinyl-biphenyl-2-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide (28.7 mg, 0.0567 mmol, 1 eq) was dissolved in EtOH (1 mL) and Pd/C (10% Pd, -50% H2O, 6.03 mg, ca 0.00567 mmol, ca 0.1 eq) was added.
  • Example 1.85 (S)-1-[2-(4-Cyano-pyridin-3-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4- methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and 3- bromoisonicotinonitrile in analogy to Example 1.25 to give the title compound.
  • Example 1.89 to Example 1.93 were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1 ,T- biphenyl]-2-sulfonyl chloride LiCI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to Example 1.62.
  • LC-MS data of Example 1.89 to Example 1.93 are listed in the table below. The LC-MS conditions used were LC- MS (1).
  • Example 1.94 (S)-1-(4-Methyl-2-[1,2,3]triazol-2-yl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide:
  • 2-(2-(Benzylthio)-5-methylphenyl)-2H-1,2,3-triazole 2-(2-bromo-5-methylphenyl)-2H-1 ,2,3-triazole (100 mg, 0.42 mmol, 1 eq), benzyl mercaptan (0.0498 mL, 0.42 mmol, 1 eq) and DIPEA (0.147 mL, 0.84 mmol, 2 eq) were dissolved in degassed dioxane (1.6 mL) and the resulting mixture was stirred at 95 °C.
  • 2-Bromo-2',5,6'-trimethyl-1,1'-biphenyl in a microwave vial, 4-bromo-3-iodotoluene (97%, 100 mg, 0.327 mmol, 1 eq), 2,6-dimethylphenylboronic acid (49.0 mg, 0.327 mmol, 1 eq), K2CO3 (228 mg, 1.63 mmol, 5 eq) and Pd(PPh3)4 (38.9 mg, 0.0327 mmol, 0.1 eq) were dissolved in degassed dioxane I water 4:3 (3.3 mL) and the resulting mixture was stirred at 165 °C for 20 min under microwave irradiations.
  • Example 1.100 to example 1.101 were synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1-((4-methyl- 2-(4,4, 5,5-tetramethy 1-1 , 3, 2-dioxaborolan-2-y I) pheny l)su Ifony I) py rrol idine-2-carboxami de and the appropriate bromoaryl in analogy to Example 1.96.
  • LC-MS data of Example 1.100 to Example 1.101 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • 5-(Benzylthio)-4-chloro-2-methylpyridine a mixture of 5-bromo-4-chloro-2-methylpyridine (500 mg, 2.32 mmol, 1 eq), benzyl mercaptan (292 mg, 2.32 mmol, 1 eq) and DIPEA (0.812 mL, 4.65 mmol, 2 eq) in dioxane (10 mL) was degassed with N2. The mixture was rapidly heated to 95 °C, and Pd2(dba)3 (106 mg, 0.116 mmol, 0.05 eq) and XantPhos (137 mg, 0.232 mmol, 0.1 eq) were added.
  • Example 1.104 to Example 1.109 were synthesized using the appropriate amino acid, 2'-fluoro-5-methyl-[1,T- biphenyl]-2-sulfonyl chloride LICI and 4,4-difluorocyclohexan-1-amine hydrochlororide in analogy to Example 1.62.
  • LC-MS data of example 1.104 to Example 1.109 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • (2R,3R)-3-Fluoro-1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)pyrrolidine-2-carboxylic acid to an ice- cooled soln, of (2R,3R)-1-[(tert-butoxy)carbonyl]-3-fluoropyrrolidine-2-carboxylic acid (35 mg, 0.15 mmol, 1 eq) in DCM (3 mL), HCI (4M in dioxane, 0.5 mL) was added. The resulting soln, was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure.
  • Example 1.114 to Example 1.119 were synthesized in analogy to Example 1.98 using the appropriate boronic acids.
  • LC-MS data of Example 1.1 14 to Example 1.119 are listed in the table below.
  • the LC-MS conditions used were LC-MS (1).
  • Example 1.120 2-(2'-Fluoro-5-methyl-biphenyl-2-sulfonyl)-5-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: l-(tert-Butyl) 5-ethyl 3-methyl-4,5-dihydro-1H-pyrazole-1,5-dicarboxylate: CuCI 2 (26.9 mg, 0.200 mmol, 0.2 eq) was added to a soln, of tert-butyl (E)-2-(1-chloropropan-2-ylidene)hydrazine-1-carboxylate (207 mg, 1.00 mmol, 1 eq), ethyl diazoacetate (0.363 mL, 3.00 mmol, 3 eq), and Na2CO3 (530 mg, 5.00 mmol, 5 eq) in DCM (8
  • Ethyl 1-((2'-fluoro-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-3-methyl-4,5-dihydro-1H-pyrazole-5-carboxylate to an ice-cooled soln, of (tert-butyl) 5-ethyl 3-methyl-4,5-dihydro-1 H-pyrazole-1 ,5-dicarboxylate (51.3 mg, 0.200 mmol, 1 eq) in DCM (3 mL), HCI (4M in dioxane, 0.5 mL) was added. The resulting soln, was stirred at rt overnight. The volatiles were removed under reduced pressure.
  • Example 1.121 (1S,2S,5R)-3-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-3-aza- bicyclo[3.1.0]hexane-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride, 2-bromo-4-methylbenzene-1 -sulfonyl chloride and 2-bromo-3-chloropyridine in analogy to Example 1.110 to give the title compound.
  • LC-MS (1): IR 1.176 min; [M+H] + : 524.3.
  • Example 1.122 (1S,3S,5S)-2-[2-(3-Chloro-pyridin-2-yl)-4-methyl-benzenesulfonyl]-2-aza- bicyclo[3.1.0]hexane-3-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid hydrochloride, 2-bromo-4-methylbenzene-1 -sulfonyl chloride and 2-bromo-3-chloropyridine in analogy to Example 1.110 to give the title compound.
  • LC-MS (1): IR 1.167 min; [M+H] + : 524.2.
  • Example 1.132 to Example 1.135 were synthesized using the appropriate amino acid or amino acid salt according to the procedures described in Example 1.21.
  • LC-MS data of Example 1.132 to Example 1.135 are listed in the table below.
  • the LC-MS conditions used were LC-MS (1).
  • Example 1.136 (S)-1-[4-Methyl-2-(3-methyl-pyrazin-2-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (S)-N-(4,4-difluorocyclohexyl)-N-methyl-1 -((4- methyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)pyrrolidine-2-carboxamide and 2-bromo-3- methylpyrazine in analogy to Example 1.96 to give the title compound.
  • LC-MS (1): IR 1.027 min; [M+H] + : 493.2.
  • Example 1.138 and Example 1.139 (S)-N-(4,4-difluorocyclohexyl)-1-(((Sa)-2'-fluoro-6'-methoxy-5-methyl- [1,1'-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and (S)-N-(4,4-difluorocyclohexyl)-1- (((Ra)-2'-fluoro-6'-methoxy-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide : 2-Bromo-2'-fluoro-6'-methoxy-5-methyl-1,1'-biphenyl: 4-bromo-3-iodotoluene 97% (150 mg, 0.49 mmol, 1 eq),
  • (2S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-6'-methoxy-5-methyl-[1,r-biphenyl]-2-yl)sulfonyl)-N- methylpyrrolidine-2-carboxamide (2S)-N-(4,4-difluorocyclohexyl)-1-((2'-fluoro-6'-methoxy-5-methyl-[1, 1'- biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide (61.7 mg, 0.196 mmol, 1 eq) in DCM (1.5 mL) was added to a soln, of (S)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (48.3 mg, 0.196 mmol, 1 eq), and TEA (0.0828 mL, 0.588 m
  • Example 1.142 (S)-1-[2-((2R,5S)-2,5-Dimethyl-pyrrolidin-1-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3- yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (30 mg, 0.0688 mmol, 1 eq), c/s-2,5- dimethylpyrrolidine hydrochloride (14.6 mg, 0.103 mmol, 1.5 eq) and KF (12 mg, 0.21 mmol, 3 eq) in DMF (1 mL) was heated to 140 °C for 96 h. The mixture was allowed to cool to rt. The mixture was purified by basic prep.
  • Example 1.143 to Example 1.145 were synthesized using the amine or amine salt in analogy to Example 1.142.
  • LC-MS data of Examples 1.143 to 1.145 are listed in the table below.
  • the LC-MS conditions used were LC-MS (1).
  • 1-(2-Bromo-5-methylphenyl)-3-fluoropiperidine a mixture of 4-bromo-3-iodotoluene (184 mg, 0.60 mmol, 1 eq), 3-fluoropiperidine hydrochloride (104 mg, 0.72 mmol, 1.2 eq), NaOtBu (150 mg, 1.56 mmol, 2.6 eq), XantPhos (53.7 mg, 0.090 mmol, 0.15 eq) and Pd2(dba)3 (22 mg, 0.024 mmol, 0.04 eq) in dioxane (3 mL) was heated to 90 °C for 14 h under an N2 atmosphere. The mixture was diluted with sat. aq.
  • reaction mixture was concentrated and the pale yellow solid was suspended in DCM (2 mL) and stirred at -78 °C.
  • a soln, of SO2CI2 (0.0317 mL, 0.379 mmol, 1 .2 eq) in DCM (1.3 mL) was added at rt and the reaction stirred at rt.
  • the reaction mixture was concentrated under reduced pressure.
  • Example 1.148 (2S)-N-(4,4-difluorocyclohexyl)-1-((2-(2-(methoxymethyl)piperidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20 mg, 0.0459 mmol, 1 eq), rac-2- (methoxymethyl)piperidine (62 mg, 0.46 mmol, 10 eq) and KF (48 mg, 0.83 mmol, 18 eq) in DMF (1 mL) was heated to 140 °C for 18 h.
  • Example 1.150 to Example 1.154 were synthesized using (S)-1-((2-bromo-4-methylphenyl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methy Ipy rrolidi ne-2-carboxamide and the appropriate boronic acid or boronic ester in analogy to Example 1.1.
  • LC-MS data of Example 1 .150 to Example 1 .154 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Example 1.156 and Example 1.157 (S)-1-(((Ra)-2'-Chloro-5,6'-dimethyl-[1,1'-biphenyl]-2-yl)sulfonyl)-N-(4,4- difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide and (S)-1-(((Sa)-2'-Chloro-5,6'-dimethyl-[1,r- biphenyl]-2-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide : were synthesized using 4-bromo-3-iodotoluene and (2-chloro-6-methylphenyl)boronic acid in analogy to Example 1.138 to give the title compound.
  • Example 1.158 (2S)-N-(4,4-Difluorocyclohexyl)-1-((2-(2,3-dimethylpyrrolidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-N- (4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (20.0 mg, 0.0459 mmol, 1 eq), 2,3-dimethylpyrrolidine hydrochloride (66 mg, 0.46 mmol, 10 eq) and KF (40 mg, 0.69 mmol, 15 eq) in DMF (2.8 mL) was heated to 140 °C for 1 h. The mixture was allowed to cool to rt. The crude mixture was purified by basic prep. HPLC to give the title compound.
  • Example 1.160 and Example 1.161 (S)-N-(4,4-Difluorocyclohexyl)-1-(((Ra)-2'-fluoro-5,6-dimethyl-[1,1'- biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide and (S)-N-(4,4-Difluorocyclohexyl)-1-(((Sa)-2'- fluoro-5,6-dimethyl-[1,r-biphenyl]-2-yl)sulfonyl)-N-methylpyrrolidine-2-carboxamide :
  • Methyl ((2-chloro-6-methylpyridin-3-yl)sulfonyl)-L-prolinate a soln, of 2-chloro-6-methylpyridine-3-sulfonyl chloride (1.80 g, 7.56 mmol, 1 eq) in DCM (10 mL) was added to a soln, of L-proline methyl ester hydrochloride (1.38 g, 8.32 mmol, 1 .1 eq), DIPEA (5.21 mL, 30.3 mmol, 4 eq) and DMAP (92.4 mg, 0.756 mmol, 0.1 eq) in DCM (20 mL).
  • Example 1.164 to Example 1.167 were synthesized according to the procedure described in Example 1.163 using the corresponding amine or amine salt.
  • LC-MS data of Example 1.164 to Example 1.167 are listed in the table below.
  • the LC-MS conditions used were LC-MS (1).
  • Methyl ((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate a mixture of methyl ((2-chloro- 6-methylpyridin-3-yl)sulfonyl)-L-prolinate (133 mg, 0.416 mmol, 1 eq), N-ethylisopropylamine (0.257 mL, 2.08 mmol, 5 eq) and TMP (0.709 mL, 4.16 mmol, 10 eq) was heated to 140 °C for 96 h. The mixture was allowed to cool to rt and purified by basic prep. HPLC to give the title compound.
  • LC-MS (2): IR 0.88 min; [M+H] + : 369.91.
  • tert-Butyl (1,1-difluorospiro[2.3]hexan-5-yl)(methyl)carbamate (mixture of 2 stereoisomers): NaH (ca 55% in oil, 304 mg, ca 7.6 mmol, ca 1.5 eq) was added to a soln, of tert-butyl (1 ,1-difluorospiro[2.3]hexan-5-yl)carbamate (1180 mg, ca 5.1 mmol, ca 1 eq) in DMF (20 mL) at 0 °C. The mixture was stirred for 10 min, and methyl iodide (0.631 mL, 10.1 mmol, 2 eq) was added.
  • Benzyl (1,1-difluorospiro[2.5]octan-6-yl)carbamate (mixture of 2 stereoisomers): benzyloxycarbonyl chloride (1.02 mL, 7.21 mmol, 1.5 eq) was added dropwise to a soln, of 1 , 1-difluorospiro[2.5]octan-6-amine hydrochloride (950 mg, 4.81 mmol, 1 eq) and DIPEA (1.86 g, 14.4 mmol) in DCM (30 mL) at O °C. The mixture was stirred for 30 min while warming up to rt. The solvents were removed under reduced pressure.
  • Benzyl (1,1-difluorospiro[2.5]octan-6-yl)(methyl)carbamate (mixture of 2 stereoisomers): NaH (ca 55% in oil, 146 mg, ca 3.66 mmol, ca 1.5 eq) was added to benzyl (1 ,1-difluorospiro[2.5]octan-6-yl)carbamate (720 mg, 2.44 mmol, 1 eq) in DMF (10 mL) at 0 °C. The mixture was stirred for 10 min while warming up to rt. Mel (0.354 mL, 4.88 mmol, 2 eq) was added, and the mixture was stirred for 20 min. The solvents were removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound.
  • LC-MS (2): IR 1.07 min; [M+H] + : 310.31.
  • Example 1.172 (S)-1-[6-Methyl-2-((S)-3-methyl-morpholin-4-yl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.169 using (S)-3- methylmorpholine as amine.
  • LC-MS (1): tR 1.118 min; [M+H] + : 501.3.
  • (2S)-3-((2-Chloro-6-methylpyridin-3-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to (2S)-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (97.0 mg, 0.756 mmol, 0.9 eq) in aq. 2M NaOH (1.7 mL) was added dropwise to a soln, of 2-chloro-6-methy Ipy ridiny l-3-sulfony I chloride (200 mg, 0.84 mmol, 1 eq) in THF (5 mL). The mixture was stirred at rt for 2 h, and aq.
  • (2S)-3-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2S)-3-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80 mg, ca 0.25 mmol, ca 1 eq), N-ethylisopropylamine (0.156 mL, 1.26 mmol, 5 eq) and TMP (0.43 mL, 2.5 mmol, 10 eq) was heated to 140 °C for 48 h. The mixture was allowed to cool to rt. The mixture was purified by acidic prep HPLC to give the title compound.
  • LC-MS (2): t 0.76 min; [M+H] + : 368.17.
  • Example 1.175 (S)-1-((2S,6S)-2,6,6'-Trimethyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-3'-sulfonyl)- pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized using (2S, 6S)- dimethylpiperidine hydrochloride in analogy to Example 1.170.
  • LC-MS (2): t R 1.03 min; [M+H] + : 514.5.
  • Example 1.176 (S)-1-[2-(ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (1,1-difluoro-spiro[2.5]oct-6-yl)-amide: was synthesized using 1, 1-difluorospiro[2.5]octan-6-amine as amine in analogy to Example 1.171.
  • LC-MS (1): t R 1.331 min; [M+H] + : 499.3.
  • Example 1.177 (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.169 using (3S, 5S)-dimethylmorpholine.
  • LC-MS (1): t R 1.171 min; [M+H] + : 515.4.
  • Example 1.178 (S)-1-[6-Methyl-2-(2-methyl-cyclohex-1-enyl)-pyridine-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.168 using 4, 4,5,5- tetramethyl-2-(2-methylcyclohex-1-en-1-yl)-1 ,3,2-dioxaborolane.
  • LC-MS (1): t R 1.133 min; [M+H] + : 496.3.
  • Example 1.182 (S)-1-(2-Cyclohex-1-enyl-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.168 using cyclohex-1 en-1- yl(boronic acid).
  • LC-MS (1): t R 1.127 min; [M+H] + : 482.3.
  • Example 1.184 ⁇ (S)-1-[2-(Ethyl-isopropyl-amino)-6-methyl-pyridine-3-sulfonyl]-pyrrolidin-2-yl ⁇ -thiazolidin- 3-yl-methanone: a mixture of ((2-(ethyl (isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-L-proline (24.5 mg, 0.0688 mmol, 1 eq), thiazolidine (7.36 mg, 0.0826 mmol, 1.2 eq), HATU (54.9 mg, 0.0722 mmol, 1.05 eq) and DIPEA (0.059 mL, 45 mmol, 5 eq) in DMF (0.8 mL) was stirred at rt overnight.
  • Example 1.185 to Example 1.246 were synthesized according to the procedure described in Example 1.184 using the corresponding amine or amine salt. LC-MS data of Example 1.185 to Example 1.246 are listed in the table below. The LC-MS conditions used were LC-MS (1).
  • Methyl rac-(2R*,4R*)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-4-methylpyrrolidine-2- carboxylate a mixture of methyl rac-(2R*,4R*)-1-((2-chloro-6-methylpyridin-3-yl)sulfonyl)-4-methylpyrrolidine-2- carboxylate (340 mg, 1.02 mmol, 1 eq), N-ethylisopropylamine (0.631 mL, 5.11 mmol, 5 eq) and TMP (1.74 mL, 10.2 mmol, 10 eq) was heated to 140 °C for 24 h.
  • rac-(2R*,4R*)-1-((2-(Ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-4-methylpyrrolidine-2-carboxylic acid a mixture of methyl rac-(2R*,4R*)-1-((2-(ethyl(isopropyl)amino)-6-methylpyridin-3-yl)sulfonyl)-4- methylpyrrolidine-2-carboxylate (200 mg, 0.521 mmol, 1 eq) and LIOH (25 mg, 1.04 mmol, 2 eq) in THF (2 mL) and water (1 mL) was stirred for 18 h at rt.
  • Example 1.252 (S)-1-[2-(Ethyl-isopropyl-amino)-6-trifluoromethyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (4,4-difluoro-cyclohexyl)-N-methyl-amide: a mixture of (S)-1-((2-chloro-6- (trifluoromethyl)pyridin-3-yl)sulfonyl)-N-(4,4-difluorocyclohexyl)-N-methylpyrrolidine-2-carboxamide (51 mg, 0.105 mmol, 1 eq), N-ethylisopropylamine (0.065, 0.53 mmol, 5 eq) and TMP (0.179 mL, 1.05 mmol, 10 eq) was heated to 140 °C for 72 h. The mixture was allowed to cool to rt. The mixture was purified by basic prep. HPLC to give the title compound.
  • Example 1.254 (S)-1-[2-((3S,5S)-3,5-Dimethyl-morpholin-4-yl)-6-methyl-pyridine-3-sulfonyl]-pyrrolidine-2- carboxylic acid (1,1-difluoro-spiro[2.3]hex-5-yl)-amide: a mixture of (S)-1-((2-chloro-6-methylpyridin-3- yl)sulfonyl)-N-(1 , 1 -difluorospiro[2.3]hexan-5-yl)pyrrolidine-2-carboxamide (30 mg, 0.072 mmol, 1 eq), (3S, 5S)-3,5- dimethylmorpholine (42 mg, 0.36 mmol, 5 eq) and TMP (0.596 mL, 3.57 mmol, 10 eq) was heated to 140 °C for 18 h.
  • N-(4,4-Difluorocyclohexyl)-N,3-dimethyl-4,5-dihydro-1 H-pyrazole-5-carboxamide hoydrochloride to a soln, of tert-butyl 5-((4,4-difluorocyclohexyl)(methyl)carbamoyl)-3-methyl-4,5-dihydro-1 H-pyrazole-1 -carboxylate (100 mg, 0.278 mmol, 1 eq) in DCM (2 mL) was added HCI (4M in dioxane, 2 mL). The mixture was stirred for 1 h at rt. The solvents were removed under reduced pressure to give the title compound that was used further without further purification.
  • LC-MS (2): t 0.51 min; [M+H] + : 260.33.
  • Example 1.256 (S)-1-(2-lsopropylamino-6-methyl-pyridine-3-sulfonyl)-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.169 using isopropylamine.
  • LC- MS (1): t R 1.272 min; [M+H] + : 459.2.
  • LC-MS (1): t R 1.207 min; [M+H] + : 473.3.
  • 1-(2-Bromo-5-methylphenyl)-5-cyclopropyl-1 H-pyrazole In a sealed microwave tube, 1-(2-bromo-5- methylphenyl)-5-cyclopropyl-1 H-pyrazole-4-carboxylic acid (177 mg, 0.55 mmol, 1 eq) was suspended in water (2.5 mL). Sulfuric acid (0.0619 mL, 1.16 mmol, 2.1 eq) was added and the mixture was vigorously stirred at 100 °C for 46 h. Concentrated H2SO4 (0.619 mL, 11.6 mmol, 21 eq) was added again and the reaction mixture was stirred at 100 °C for 21 h.
  • Example 1.259 (S)-1-[2-(5-Ethyl-pyrazol-1-yl)-4-methyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (4,4- difluoro-cyclohexyl)-N-methyl-amide: was synthesized in analogy to Example 1.258 using ethyl (E)-2- ((dimethylamino)methylene)-3-oxopentanoate to give the title compound as a white solid.
  • LC-MS (1): IR 1.155 min; [M+H] + : 495.2.
  • Methyl ((4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-L-prolinate methyl ((2- bromo-4-methylphenyl)sulfonyl)-L-prolinate (1000 mg, 2.76 mmol, 1 eq), PdCl2(MeCN)2 (14.6 mg, 0.0552 mmol, 0.02 eq) and SPhos (90.7 mg, 0.221 mmol, 0.08 eq) were introduced into a 250 mL round bottom flask which was evacuated and backfilled with N2.
  • Methyl ((4-methyl-2-(3-methylpyrazin-2-yl)phenyl)sulfonyl)-L-prolinate methyl ((4-methyl-2-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-L-prolinate (50 mg, 0.115 mmol, 1 eq), 2-bromo-3- methylpyrazine (30.4 mg, 0.172 mmol, 1 .5 eq), NaHCOa (29 mg, 0.344 mmol, 3 eq) and Pd(PPha)4 (13.7 mg, 0.0115 mmol, 0.1 eq) were dissolved in degassed DME/water 4: 1, and the resulting mixture was stirred at 85 °C for 3 h.

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Abstract

La présente invention concerne de nouveaux dérivés d'arylsulfone et de sulfanone de formule (I), dans laquelle R1, R2, RB1, RB3, X1, X2, X3, X4, le cycle A et le cycle B sont tels que décrits ici, leurs sels pharmaceutiquement acceptables et leur utilisation comme produits pharmaceutiques. L'invention concerne également des aspects connexes, y compris des processus de préparation des composés, des compositions pharmaceutiques contenant un ou plusieurs composés de formule (I), et leur utilisation comme agonistes du récepteur de l'orexine-2 (ci-après également appelé OX2R), et en particulier comme agonistes du récepteur de l'orexine-2 humain (ci-après également appelé hOX2R).
PCT/EP2025/061059 2024-04-24 2025-04-23 Dérivés d'arylsulfone et de sulfanone utilisés en tant que modulateurs du récepteur de l'orexine Pending WO2025224168A1 (fr)

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