Macrocyclic orexin agonists

Abstract

The present invention relates to aryl thiol macrocycles of Formula (I) wherein R1, R2, RA1, X1, X2, X3, X4, L, X5, and Ring A are as described in the description, to pharmaceutically acceptable salts thereof, and to 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.

Description

Macrocyclic Orexin AgonistsThe present invention relates to novel aryl thiol macrocycles 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 (OX-A) and orexin B (OX-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. 2005, 25(28):6716- 20). They send excitatory projections to 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. Different 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. 2007, 8(3): 171 -81 )). OX-A levels in the brain extracellular and cerebrospinal fluid (CSF) follow a circadian rhythm: they rise during the wake period and drop rapidly during sleep. Increasing orexin levels are necessary to compete with the increasing sleep pressure that builds up during long periods of wakefulness, preventing from falling asleep (Gotter AL et al.; The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold; BMC Neurosci. 2013, 14:90; Modirrousta M et al.; Orexin and MCH neurons express c-Fos differently after sleep deprivation vs. recovery and bear different adrenergic receptors; Eur J Neurosci. 2005, 21(10)2807-16; Zeitzer JM et al.; Circadian andhomeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness; J Neurosci. 2003, 23(8):3555-60).Moreover, orexin neurons integrate a variety of signals related to the 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). For this purpose, they do not only follow a circadian related pattern of activation, but also a behaviour-related burst of firing and are, for example, particularly active in periods of heightened arousal associated with emotion and social interaction (Blouin AM et al.; Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction; Nat Commun. 2013, 4:1547). Evidence from human and animal studies have demonstrated that 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. 1999, 98(3):365-76; 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; Thannickal TC et al.; Reduced number of hypocretin neurons in human narcolepsy; Neuron. 2000, 27(3):469-74). In human, 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 (Dauvilliers Y et al.; Narcolepsy and Other Central Hypersomnias; Continuum (Minneap Minn). 2017, 23(4, Sleep Neurology):989-1004). Several genetic animal models (in both mice and dogs) showed that disruption of orexin signaling leads to a narcoleptic phenotype with excessive daytime sleepiness (fragmented wakefulness) and cataplexy (Lin L et al.; The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene; Cell. 1999, 98(3):365-76; Willie JT et al.; Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes; Neuron. 2003, 38(5):715-30). Central administration of OX-A or ectopic expression of the prepro-orexin transgene in the brain of orexin neuron-ablated mice are able to reverse the narcoleptic phenotype (Mieda M et al.; Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice; Proc Natl Acad Sci U S A. 2004, 101 (13):4649-54). Those data suggest that an orexin receptor agonist would be an appropriate treatment for narcoleptic patients.In addition, 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). Furthermore, optogenetic or chemogenetic studies showed that stimulation of orexin neurons reduced the latency in sleep-to-wake transition from both NREM and REM sleep and induced wakefulness with a very short latency (Adamantidis AR et al.; Neural substrates of awakening probed with optogenetic control of hypocretin neurons; Nature. 2007, 450(7168) :420-4; Sasaki K et al.; Pharmacogenetic modulation of orexin neurons alters sleep / wakefulness states in mice; PLoS One. 2011 , 6(5):e20360).Altogether, it suggests that 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).These can be seen in sleep disorders such as the disorders of hypersomnolence. Based on the international classification of sleep disorders, 3rdedition (ICSD-3) (Sateia MJ; International classification of sleep disorders-third edition: highlights and modifications; Chest. 2014, 146(5):1387-1394), central disorders of hypersomnolence include narcolepsy (including narcolepsy type 1 and narcolepsy type 2), 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 destroys orexin-producing neurons. However, symptoms of narcolepsy (or secondary narcolepsy) can occur during the course of other neurologic disorders and can 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 hypothalamic area is involved) (Kanbayashi T et al.; The pathophysiologic basis of secondary narcolepsy and hypersomnia; Curr Neurol Neurosci Rep. 2011, 11 (2):235-41 ; Nishino S et al.; Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin / orexin system; Sleep Med Rev. 2005, 9(4):269-310). Reduced orexin levels in CSF were often seen in those symptomatic narcolepsy and EDS cases. Other immune-mediated disorders can show a disruption of orexin neurotransmission with patients presenting symptoms reminiscent of narcolepsy (Fronczek R et al.; The orexin / hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms; Handb Clin Neurol. 2021 , 180:343-358). For some of them, destruction of part of the orexin neurons on top of other cell types have been demonstrated. For example, 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. 2009, 66(12): 1563-6), 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).In neurodegenerative disease, EDS and other sleep disturbances are commonly reported. Loss of orexin neurons has been described in several neurodegenerative diseases and is suggested to contribute to EDS and sleep disturbances. Such neurodegenerative diseases include Alzheimer's (Fronczek R et al.; Hypocretin (orexin) loss in Alzheimer's disease; Neurobiol Aging. 2012, 33(8): 1642-50), Parkinson's (Fronczek R et al.; Hypocretin (orexin) loss in Parkinson's disease; Brain. 2007, 130(Pt 6): 1577-85; Fronczek R et al.; Hypocretin (orexin) loss and sleep disturbances in Parkinson's Disease; Brain. 2008, 131(Pt 1):e88), Lewy body dementia (Kasanuki K et al.; Neuropathological investigation of hypocretin expression in brains of dementia with Lewy bodies; Neurosci Lett. 2014, 569:68-73), Perry syndrome (Mishima T et al.; Reduced orexin immunoreactivity in Perry syndrome and multiple system atrophy; Parkinsonism Relat Disord. 2017, 42:85-89), multiple system atrophy (Benarroch EE et al.; Involvement of hypocretin neurons in multiple system atrophy; Acta Neuropathol. 2007, 113(1)75-80), amyotrophic lateral sclerosis (Gabery S et al., Loss of metabolism and sleep regulating neuronal populations expressing orexin and oxytocin in the hypothalamus in amyotrophic lateral sclerosis; Neuropathol Appl Neurobiol. 2021, 47(7):979-89),and Huntington's diseases (Petersen A et al.; Orexin loss in Huntington's disease; Hum Mol Genet. 2005, 14(1):39-47).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; Gandhi KD et al.; Excessive Daytime Sleepiness: A Clinical Review; Mayo Clin Proc. 2021 , 96(5): 1288-1301). It is especially the case when the patient needs to be awake but his alertness level, secondary to his internal body clock, is at its nadir.Likewise, 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). Particularly for obstructive sleep apnea (OSA) the dysregulation of the orexin system could play a role in its pathogenesis (Wang W et al.; Orexin: a potential role in the process of obstructive sleep apnea; Peptides. 2013, 42:48-54). Low levels of OX-A in plasma were reported in patients suffering from OSA (Busquets X et al.; Decreased plasma levels of orexin-A in sleep apnea; Respiration. 2004, 71(6)575-9). In addition, in the orexin knockout narcolepsy mouse model, the frequency of spontaneous sleep apneas increased compared to wild-type mice (Nakamura A et al.; Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice; J Appl Physiol (1985). 2007, 102(1):241-8).Different from EDS, fatigue is a lack of energy ("an overwhelming sense of tiredness, a feeling of physical or mental exhaustion") with a reduced ability to initiate or perform physical activities that would have previously been easily accomplished, and is accompanied by mental fatigue with poor concentration and memory. Fatigue is not significantly improved by increased rest or sleep and is generally associated with inappropriate episodes of sleep during the day. It is observed in a number of disorders including infections, chronic inflammatory diseases (Arron HE et al.; Myalgic encephalomyelitis / chronic fatigue syndrome: the biology of a neglected disease; Frontiersimmunology. 2024, 15: 1386607), autoimmune diseases (Manjaly Z-M et al.; Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis; J Neurol Neurosurg Psychiatry. 2019, 90:642-51; Ahn GE et al.; Fatigue in systemic lupus erythematosus; Int J Clin Rheumatol. 2012, 7(2): 217-27), cancer and chemotherapy (Bower JE & Lamkin DM; Inflammation and cancer-related fatigue: Mechanisms, contribution factors, and treatment implications; Brain Beh Immunity. 2013, 30:S48-57), and neurodegenerative and neurological diseases (Kluger BM et al.; Fatigue and fatigability in neurologic illnesses; Neurology. 2013, 80:409-16). Persistent physical and mental fatigue is a prominent symptom of myalgic encephalomyelitis / chronic fatigue syndrome (Arron HE et al.; Myalgic encephalomyelitis / chronic fatigue syndrome: the biology of a neglected disease; Frontiers Immunology. 2024, 15: 1386607). Dysregulation of the orexin system could contribute to fatigue. In rodents, fatigue (or sickness behavior in animals) induced by lipopolysaccharide was associated with reduced activity of orexin neurons and a reduction of OX-A in the CSF (Grossberg AJ et al.; Inflammation-induced lethargy is mediated by suppression of orexin neuron activity; J Neurosci. 2011 , 31 (31): 11376-86; Gaykema RPA & Goehler LE; Lipopolysaccharide challenge- induced suppression of Fos in hypothalamic orexinneurons: Their potential role in sickness behavior; Brain Beh. Immunity. 2009, 23:926-30). Intracerebroventricular administration of OX-A in lipopolysaccharide-treated rats restored normal home-cage exploratory behavior. Similar findings were retrieved in tumor-bearing rats and chemotherapy-treated mice (Weymann KB et al.; A role of orexin in cytotoxic chemotherapy-induced fatigue; Brain Beh. Immun. 2014, 37:84-94) indicating that the reduction of orexin signaling could play a role in chronic disease. In human, Bardsen et al., (Bardsen K et al.; Interleukin-1 -related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjogren's syndrome; J Neuroinflammation. 2019, 16(1): 102) showed that OX-A level was decreased in CSF of patients suffering from primary Sjogren's syndrome, a chronic autoimmune disease clinically characterized by inflammation of the exocrine glands where fatigue is an important symptom (Segal B et al.; Prevalence, severity, and predictors of fatigue in subjects with primary Sjogren's syndrome; Arthritis Rheum. 2008, 59(12): 1780-7).These findings suggest that a dysfunction of the orexin system could contribute to fatigue and that an orexin receptor agonist could help chronically ill patients with fatigue and improve their quality of life.Traumatic brain injury (TBI) can induce disorders of consciousness (DOC) such as syndromes of coma, vegetative state, and minimally conscious state (O'Donnell JC 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 PatientsWith 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. Given the orexin system’s projections to the wake-promoting areas of the brain and its contribution to the stabilization of wakefulness / arousal, it is well placed to support and regulate consciousness. Interestingly, in patients with acute moderate and severe TBI, an 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). Preclinically, in a mouse model of TBI, electromagnetically controlled cortical impact depressed orexin levels in both the hypothalamus and hippocampus, and the diurnal fluctuation amplitudes of orexins were blunted (Willie JT et al.; Controlled cortical impact traumatic brain injury acutely disrupts wakefulness and extracellular orexin dynamics as determined by intracerebral microdialysis in mice; J Neurotrauma. 2012, 29(10): 1908-21). Those data indicate that the orexin system is dysregulated following TBI and an orexin receptor agonist could be a useful therapeutic approach.In addition, in a model of unconscious rats induced by acute alcohol intoxication, i.c.v. administration of OX-A or OX-B reduced the duration of righting reflex loss, shortened the coma time, and decreased the delta signal of EEG (Jia X et al.; Arousal effects of orexin A on acute alcohol intoxication-induced coma in rats; Neuropharmacology. 2012, 62(2):775-83). It suggests that orexin receptor agonists could have an arousal-promoting effect in coma induced by acute alcohol intoxication. Furthermore, intranasal or i.c.v. administration of OX-A facilitated the recovery of arousal in 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. Additionally, in this model of cardiac arrest, OX-A did not only accelerate arousal and behavior recovery, but it also had some anti-inflammatory effects. Other studies raised the potential role of the orexin system in the regulation of inflammation. For instance, Ogawa et al. (Ogawa Y et al.; Peripherally administered orexin improves survival of mice with endotoxin shock; Elife. 2016, 5) showed that, in a model of septic shock in mice, administration of OX-A helped for survival and recovery and that excessive cytokine production was inhibited. In a mouse model of intracerebral hemorrhage, 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. In rodent models of cerebral ischemia Ox-A reduced the neuronal damage and improved neuronal deficits (Harada S et al.; Effect of orexin-A on post-ischemic glucose intolerance and neuronal damage; J. Pharmacol. Sci. 2011, 115:155-63; Yuan LB et al.; Neuroprotective effect of orexin-A is mediated by an increase of hypoxia- inducible factor-1 activity in rat; Anesthesiology. 2011, 114: 340-54). In patients with subarachnoid hemorrhage OX-A levels are higher in patients who do not develop delayed ischemic neuronal deficit (Dohi K et al.; CSF hypocretin-1 / orexin-A concentrations in patients with subarachnoid hemorrhage (SAH); Peptides. 2005, 26:2339- 43).Moreover, it is also suggested that 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. 2008, 105(4): 1309-14; Zhang LN et al.; Orexin-A facilitates emergence of the rat from isoflurane anesthesia via mediation of the basal forebrain; Neuropeptides. 2016, 58:7-14; Kushikata T et al.; Orexinergic neurons and barbiturate anesthesia; Neuroscience. 2003, 121 (4):855-63).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. 2003, 144(9):3774-8; Yamanaka A et al.; Hypothalamic orexin neurons regulate arousal according to energy balance in mice; Neuron. 2003, 38(5):701 - 13). The orexin system is suggested to coordinate the behavioral / wakefulness response to the energy needs (Latifi B et al.; Sleep-Wake Cycling and Energy Conservation: Role of Hypocretin and the Lateral Hypothalamus in Dynamic State-Dependent Resource Optimization; Front Neurol. 2018, 9:790; Chieffi S et al.; Orexin System: The Key for a Healthy Life; Front Physiol. 2017, 8:357). Interestingly, narcoleptic mice show a dysregulation of energy homeostasis. Those 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). In addition, the prevalence of obesity is also increased in narcoleptic patients (Mohammadi S et al.; Metabolic profile in patients with narcolepsy: a systematic review and meta-analysis; Sleep Med. 2021 , 81 :268-284). Studies in rodent models of diet-induced obesity showed that central administration of OX-A protects against obesity (Perez-Leighton CE et al.; Behavioral responses to orexin, orexin receptor gene expression, and spontaneous physical activity contribute to individual sensitivity to obesity; Am J Physiol Endocrinol Metab. 2012, 303(7): E865-74). Reduced Ox-A was also reported in patients of anorexia nervosa (Steward T et al., Reduced Plasma Orexin-A Concentrations are Associated with Cognitive Deficits in Anorexia Nervosa; Sci Rep. 2019, 9(1): 3377-91).Altogether it suggests that an orexin receptor agonist could be an interesting therapeutic option for the treatment of disease associated with dysregulation of feeding behaviors or energy homeostasis.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. On the other hand, the orexin neurons also project toareas involved in learning and memory processing such as the hippocampus (Peyron C et al.; Neurons containing hypocretin (orexin) project to multiple neuronal systems; J Neurosci. 1998, 18(23):9996-10015) which suggest a potential direct effect. Preclinical data have shown that activation of the orexin system can be beneficial for learning and memory. For example, mice data 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. 2013, 33(12):5275-84). Intranasal administration of OX-A improved the performance altered by sleep loss on a short-term memory task in sleep-deprived rhesus monkeys without altering task performance in alert non-sleep-deprived animals (Deadwyler SA et al.; Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates; J Neurosci. 2007, 27(52): 14239-47). In addition, i.c.v. injection of OX-A in wild type mice improved memory processing in 2 different avoidance tasks but also improved memory performance in the senescence-accelerated mouse (SAMP8) strain showing age-related deficits in learning and memory (Jaeger LB et al.; Effects of orexin-A on memory processing; Peptides. 2002, 23(9): 1683-8).Cognitive impairment is a common feature of several neuropsychiatric / neurological disorders and of 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 (Calva CB et al.; Intranasal administration of orexin peptides: Mechanisms and therapeutic potential for age-related cognitive dysfunction; Brain Res. 2020, 1731 : 145921 ; Calva CB et al.; Effects of Intranasal Orexin-A (Hypocretin-1) Administration on Neuronal Activation, Neurochemistry, and Attention in Aged Rats; Front Aging Neurosci. 2019, 11 :362) suggesting a therapeutic benefit of orexin receptor agonist for age-related cognitive disorders.Furthermore, local intracerebral infusion of OX-A was able to reduce distractor-induced decreases in attention performance in rats (Zajo KN et al.; Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons; Psychopharmacology (Berl). 2016, 233(4):639-47) suggesting that an orexin-receptor agonist could be useful for the treatment of disorders with attentional deficits. Serum OX-A levels are lower in children with attention deficit hyperactivity disorder, especially in the inattentive group (Baykal s et al., Decreased serum orexin A levels in drug-naive children with attention deficit and hyperactivity disorder; Neurol Sci. 2019, 40(3): 593-602). Additionally, ADD symptoms are more frequent in children and adults with narcolepsy (Miano S et al., The sleep phenotypes of attention deficit hyperactivity disorder: the role of arousal during sleep and implications for treatment; Med Hypotheses. 2012; 79(2): 147-53).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 stressresponse and the development of coping strategy. Dysregulation of those processes can lead to neuropsychiatric disorders in which orexin receptor agonists could provide beneficial effects.As an example, 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 and schizophrenia, 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 (Liang S et al., anhedonia in depression and schizophrenia: Brain reward and aversion circuits; Neuropsychiatric Disease and Treatments. 2022, 18:1385-96). 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. 2020, 118:384-396). In 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). In animal 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. 2008, 28(12):3071 -5; Nocjar C et al.; The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus; Neuroscience. 2012, 218:138-53). In patients with major depressive disorder (MDD), lower levels of OX-A in the CSF were reported (Brundin L et al.; Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder; Eur Neuropsychopharmacol. 2007, 17(9):573-9) and depressed patients show blunted diurnal variation in CSF orexin levels (Salomon RM et al.; Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects; Biol Psychiatry. 2003, 54(2):96-104).Similarly, studies in animals and humans suggest that abnormal orexin function could contribute to the pathogenesis of post-traumatic stress disorder (PTSD). In rat models of PTSD, decreased activation of orexin neurons during the stressful event predicted the development of PTSD-like symptoms. Activating the orexin system after the stressful event prevented or alleviated PTSD-like symptoms while blocking Hcrt receptors after the stressful event exacerbated PTSD-like symptoms (Cohen S et al., Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder; Transl Psychiatry. 2016,6(10): e917; Han D et al., Mechanisms of Memory Impairment Induced by Orexin-A via Orexin 1 and Orexin 2 Receptors in Post-traumatic Stress Disorder Rats; Neurosci. 2020, 432:126-36). In humans, decreased plasma and CSF concentration of OX-A has been reported in individuals with combat-related PTSD compared to healthy controls (Strawn JR et al., Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat- related posttraumatic stress disorder; Psychoneuroendocrinology. 2010, 35(7): 1001-7).In addition, in suicidal attempters, low levels of OX-A in the CSF were correlated with psychiatric symptoms of depression such as lassitude, slowness of movement and higher rating of the overall illness (Brundin L et al.; Orexin and psychiatric symptoms in suicide attempters; J Affect Disord. 2007, 100(1-3)259-63).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. Accordingly, 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)). In addition, 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). Interestingly, lower CSF orexin levels were reported in patients suffering from cluster headaches (Barloese M et al.; Reduced CSF hypocretin-1 levels are associated with cluster headache; Cephalalgia. 2015, 35(10):869-76) and the prevalence of migraine is increased in narcoleptic patients (Dahmen N et al.; Increased frequency of migraine in narcoleptic patients: a confirmatory study; Cephalalgia. 2003, 23(1):14-9).Overall, it suggests that orexin receptor agonists could have beneficial effect in the therapeutic approach against pain.In addition, orexin receptor agonists could be a promising treatment option for daytime function deficits in disorders associated with symptoms of EDS, fatigue, reduced vigilance, attention, motivation or hedonic drive, altered stress regulation or emotions, and pain, with concomitant use of an orexin receptor antagonists at bedtime for the treatment of accompanying sleep disturbances such as in psychiatric disorders (depression, schizophrenia, PTSD, anxiety (Freeman D et al.; Sleep disturbances and psychiatric disorders; Lancet Psychiatry. 2020, 7:628-37)), neurodegernerative disorders (Alzheimer’s disorder, Dementia with Lewy bodies, Huntington’s disease, Parkinson’s disease (Fifel K & Videnovic A; Circadian and sleep dysfunctions in neurodegenerative disorder - An update; Front Neurosci. 2021 , 14:627330; Anghel L et al.; Sleep disorders associated with neurodegenerative diseases; Diagnostic. 2023, 13:2898), circadian rhythm sleep wake disorders (Kim MJ et al., Circadian rhythm sleep disorder; J Clin Outcomes Manag. 2013, 20(11): 513-28), sleep related breathing disorders (Liu J et al., Pharmacological interventions for the treatment of obstructive sleep apnea syndrome; Front Med. 2024,11 :1359461), and pain (Bigatti SM et al., Sleep isturbances in fibromyalgia syndrome: relationship to pain and depression; Arthritis Rheum. 2008, 59(7):961-67):Orexin receptor antagonists are well documented, such as, for example, in WO 2010 / 131192.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 (English-language family member US 2021 / 0385345) discloses substituted pyrrolidine compounds having an orexin type 2 receptor agonist activity. WO 2019 / 117148 (English-language family member US 2021 / 0078955) 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. Macrocyclic orexin receptor agonists are reported in WO 2021 / 108628, WO 2022 / 051583, WO 2022 / 094012, WO 2022 / 109117, WO 2022 / 140316, WO 2022 / 140317, WO 2022 / 232025, WO 2022 / 251302, and WO 2022 / 251304. Orexin receptor agonists are further reported in JP2022012861 , JP2022064180, US8258163, WO 2000 / 047580, WO 2014 / 006402, WO 2015 / 088000, WO 2015 / 152367, WO 2016 / 133160, WO 2016 / 199906, WO 2018 / 164192,WO 2019 / 112007, WO 2019 / 191327, WO 2020 / 004536, WO 2020 / 158958, WO 2020 / 167701 , WO 2021 / 026047,WO 2021 / 048821, WO 2021 / 048822, WO 2021 / 107023, WO 2021 / 065893, WO 2021 / 106975, WO 2022 / 014680,WO 2022 / 040058, WO 2022 / 040070, WO 2022 / 051596, WO 2022 / 119888, WO 2022 / 132696, WO 2022 / 140317,WO 2022 / 187231, WO 2022 / 207935, WO 2022 / 233872, WO 2022 / 250108, WO 2022 / 269049, WO 2023 / 017180,WO 2023 / 167865, WO 2023 / 167925, WO 2023 / 199091, W02023 / 204308, and WO 2023 / 232966.The preparation of N-tosylprolinamides is reported in Walther K. et al. (J. Prakt. Chem, 1987, 329(5), 859-870). Selected N-sulfonyl indoline derivatives having affinity for the vasopressin and ocytocin receptors are described in US 5,338,755, US 5,397,801, US 5,481 ,005, EP 0 469 984, and WO 1993 / 003013. Synthesis of acyl hydrazides has been described in Singh et al. (Asian J. Org. Chem., 2023, 12(6), 135-140, doi.org / 10.1002 / ajoc.202300115). Selected pyrrole sulfone derivatives are described as reverse transcriptase inhibitors (Silvestri R. et al., II Farmaco, 2004, 59, 201-210; WO 1996 / 033171; WO 2008 / 054605) and indole sulfones as modulators G-protein couple receptor GPR119 (WO 2009 / 105722). Certain thiazolidine sulfonamides are disclosed as prostaglandin F receptor modulators (US 2008 / 255094). WO 2016 / 004180 discloses quinoline and quinazoline sulfonamides as O-GIcNAc transferase inhibitors. Certain N-cyclic sulfonamide derivatives are reported as inhibitors / antagonists of STAT3 (Lopez-Tapia F. et al., ACS Med. Chem. Lett., 2018, 9, 250-255; WO 2010 / 141805; WO 2012 / 018868; WO 2018 / 136935; US 10, 196,373 B2), of TRPA1 (Chen H. et al., J. Med. Chem., 2018, 61 , 3641-3659; WO 2010 / 141805; WO 2013 / 108857 (US 2014 / 0329796; EP2805718); WO 2014 / 098098; WO 2015 / 052264; WO 2016 / 128529; WO 2018 / 015411), of CCR-9 (WO 2004 / 073634; US 2004 / 180892; US 2005 / 49286; US2007 / 293503), of gamma secretase (WO 2005 / 11354 , or of bradykin B2 (US 6,071,917, WO 98 / 003503), or as binding VLA-4 (US 6,583,139 B1; WO 98 / 053814; WO 99 / 064395). Selected azetidine sulfonamides are further reported as STAT3 inhibitors (Brotherton-Pleiss C. et al., J. Med. Chem., 2021, 64, 695-710; WO 2021 / 016333). WO 2018 / 015411 discloses certain sulfonylcycloalkyl compounds as TRPA1 modulators. Selected thiol pyrrolidine derivatives are reported as metalloprotease inhibitors in WO 2002 / 06222 / US 2002 / 049243. Sulfone-comprising pyrrolidin-2-one derivatives are disclosed as inhibitors of Factor XA in WO 2002 / 100886. Thiazolidine and piperazine carboxamide derivatives are disclosed as modulators of the prostaglandin F receptor in WO 2003 / 082278 and WO 2004 / 071390. Piperazine carboxamide derivatives are further disclosed as NS5B enzyme inhibitors in Gentles et al. (Bioorganic Med. Chem. Letters, 2011, 21, 3142-3147). Thiazolidine derivatives are further disclosed as steroid sparring agents in WO 2005 / 097162. Diazobicyclic sulfone derivatives as inhibitors of FK506 binding proteins are disclosed in WO 2015 / 110271 and WO 2021 / 175848. Sulfonamides antagonising N- type calcium channels are disclosed in WO 2005 / 068448. Synthesis of sulfone-comprising macrocycles is described in Osipyan A. et al. (J. Org. Chem., 2018, 83, 9707-9717) and Reutskaya E. et al. (J. Org. Chem., 2021, 86, 5778-5791). 1) A first aspect of the invention relates to compounds of Formula (I) wherein^ Ring A (A in Formula (I)) is a 6-membered aromatic ring, wherein: ^ RA1represents hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), halogen (notably bromo, chloro or fluoro), monocyclic (C3-4)cycloalkyl, or (C1)fluoroalkyl; [in particular RA1represents hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), or halogen (notably chloro or fluoro)]; ^ X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen (notably fluoro), (C1-3)alkyl (notably methyl), or (C1-3)alkoxy (notably methoxy);> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen (notably fluoro); and> X5represents C;[in particular Ring A represents 6-methyl-pyridin-2, 3-diyl, 4-methyl-phen-1 ,2-diyl, 3-fluoro-4-methyl- phen-1 ,2-diyl, 5-methy l-pyrazi n-2, 3-d iyl, 3-methoxy-4-methyl-phen-1 ,2-diyl, 6-fluoro-4-methyl-phen- 1 ,2-diyl, 4-chloro-phen-1,2-diyl, phen-1,2-diyl, 4-fluoro-phen-1 ,2-diyl, 3,4-difluoro-phen-1 ,2-diyl, 4- fluoro-3-methyl-phen-1,2-diyl, 3-fluoro-4-methoxy-phen-1 ,2-diyl, or 3-fluoro-4-methyl-phen-1 ,2-diyl]; and L represents:> linker group L1, wherein the backbone of said linker group L1is linear and consists of a total of 3 to 6 (notably 4 or 5) backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 (notably 3 to 5) carbon atoms and 0 to 2 (notably 0 or 1) heteroatoms independently selected from 0, N or S; wherein said backbone is saturated or partially unsaturated (notably is saturated or mono-unsaturated); wherein said backbone is unsubstituted, or mono-, di- or tri- substituted (notably unsubstituted, or mono- or di-substituted; especially mono- or di-substituted); wherein the substituents are independently selected from the group consisting of:■ (C1-6)alkyl (notably methyl, ethyl, n-propyl, or isopropyl; especially methyl);■ (C3-6)cycloalkan-1,1-diyl (notably cyclopropan-1 ,1 -diyl);■ (C3-6)cycloalkyl (notably cyclopropyl);■ hydroxy;■ halogen (notably fluoro); and, in addition,■ (C1-3)fluoroalkyl (notably trifluoromethyl);> or linker group L2, wherein the backbone of said linker group L2consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 (notably 1) heteroatom independently selected from 0, N or S (notably 0 or N); wherein said backbone is saturated or partially unsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6-membered saturated, partially unsaturated or aromatic cyclic moiety comprising a total of 0 to 3 heteroatoms independently selected from 0, N or S; wherein notably said cyclic moiety represents:■ (C3.6)cycloalkan-diyl (notably (C3.6)cycloalkan-l ,2-diyl or (C3_6)cycloalkan-1 ,3-diyl; in particular cyclopropan-1 ,2-diyl, cyclobutan-1 ,2-diyl, cyclopentan-1,2-diyl, cyclohexan- 1 ,2-diyl, cyclobutan-1 , 3-diyl, cyclopentan-1, 3-diyl, or cyclohexan-1 ,3-diyl);■ phen-diyl (notably phen-1 ,2-diyl);■ 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho or in meta position relative to one another (in particular such 5- or 6-membered heterocycloalkan-diylrepresents pyrrolidin-1 ,3-diyl, piperidin-1, 3-diyl, tetrahydrofuran-2, 3-diyl, or tetrahydrofuran-3,4-diyl); or■ 5- or 6-membered heteroaryl-diyl wherein said heteroaryl-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular such 5- or 6-membered heteroaryl-diyl represents 1 H-pyrazol-1 ,3-diyl, pyridin- 2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, or 1 ,3,4-oxadiazol-2,5-diyl); wherein L2is unsubstituted, or mono- or di-substituted (notably unsubstituted or mono- substituted); wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl) and halogen (notably chloro);[in particular said cyclic moiety represents cyclopropan-1 ,2-diyl, cydobutan-1 ,2-diyl, cyclopentan- 1 ,2-diyl, cydohexan-1,2-diyl, cyclobutan-1, 3-diyl, cyclopentan-1, 3-diyl, cydohexan-1,3-diyl, pyrrolidin-1 , 3-diyl, piperidin-1, 3-diyl, 1H -pyrazol-1, 3-diyl, tetrahydrofuran-2, 3-diyl, tetrahydrofuran-3,4-diyl, pyridin-2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, 1 ,3,4-oxadiazol-2,5-diyl, phen- 1 ,2-diyl, or 4-chloro-1 H-pyrazol-1 ,3-diyl];❖ or the fragmentFormula (l-B) wherein> Ring A (A in Formula (l-B)) represents a 6-membered aromatic ring, wherein:■ X2represents CH or N (notably CH); and■ RA1represents independently hydrogen, (C1-3)alkyl (notably methyl), C1-3) alkoxy (notably methoxy), halogen (notably chloro or fluoro), monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl; [in particular RA1represents methyl]; and Ring B (B in Formula (l-B)) represents a 5- to 7-membered (in particular 6-membered) heterocyclic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 or 2 ring heteroatoms; wherein said heteroatoms are independently selected from N, 0, or S; [in particular such Ring A and Ring B together form 2,3-dihydrobenzofuran-2,7-diyl, chroman-2,8- diyl, 1 ,2,3,4-tetrahydroquinolin-2,8-diyl, or 2,3,4,5-tetrahydrobenzo[b]oxepin-2,9-diyl; in particular such Formula (l-B) represents 4-methyl-2,3-dihydrobenzofuran-2,7-diyl, 5-methyl-chroman-2,8-diyl, 5-methyl-1 , 2,3,4-tetrahydroq u inolin-2, 8-diyl, or 6-methyl-2,3,4,5-tetrahydrobenzo[b]oxepin- 2,9-diyl];> Ring A (A in Formula (l-B)) represents a 6-membered aromatic ring, wherein:■ X2represents CH or N (notably CH); and■ RA1represents independently hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), halogen (notably chloro or fluoro), monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl; [in particular RA1represents methyl]; and Ring B (B in Formula (l-B)) represents a 5-membered heteroaromatic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 to 3 (preferably 2) ring heteroatoms; wherein said heteroatoms are independently selected from N, 0, or S; [in particular such Ring A and Ring B together form benzo[d]thiazol-2,4-diyl, imidazo[1 ,2-a]pyridin-2, 8-diyl, or 2H-indazol- 2,7-diyl; in particular such Formula (l-B) represents 7-methyl-benzo[d]thiazol-2,4-diyl, 5-methyl- imidazo[1,2-a]pyridin-2, 8-diyl, or 4-methyl-2H-indazol-2,7-diyl]; or> Ring A (A in Formula (l-B)) represents a 6-membered aromatic ring, wherein:■ X2represents CH or N (notably CH); and■ RA1represents independently hydrogen, (C1-3)alkyl (notably methyl), C1-3) alkoxy (notably methoxy), halogen (notably chloro or fluoro), monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl; [in particular RA1represents methyl]; and Ring B (B in Formula (l-B)) represents a 6-membered heteroaromatic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 or 2 ring heteroatoms; wherein said ring heteroatoms are N; [in particular such Ring A and Ring B together form quinolin-2, 8-diyl; in particular such Formula (l-B) represents 5-methyl-quinolin-2,8-diy]; and L3represents:> a linear linker group; wherein L3consists of a total of 3 or 4 backbone atoms; wherein said backbone atoms are independently selected from 3 or 4 carbon atoms and 0 or 1 heteroatom independently selected from 0, N or S (notably 0); wherein said backbone is saturated or mono- unsaturated; wherein said backbone is unsubstituted or mono-substituted with (C1-3)alkyl (notably methyl) or halogen (notably fluoro);X3represents SO2 or S(=O)(=N R3), wherein R3represents hydrogen, (C1-3)alkyl (notably methyl including methyl- c / 3), monocyclic (C3.6)cycloalkyl, or phenyl; [in particular X3represents SO2, S(=O)(=NH), S(=0)(=N(CH3)), or S(=O)(=N(CD3))];X4represents:> NRN1; wherein: o RN1represents hydrogen or (C1-3)alkyl (notably methyl); ando R1represents (C1-5)alkyl (notably methyl, isopropyl, sec-butyl, or n-butyl) or - (CH2)n-(C3- 4)cycloalkyl wherein n represents the integer 0 or 1 (notably such — (CH2)n-(C3-4)cycloalkyl represents cyclopropyl or cyclopropyl-methyl);> NRN1; wherein R1and RN1together form a ring comprising X4, herein Ring E, wherein said Ring E represents: o a 4- to 6-membered (notably 5- or 6-membered) saturated monocyclic heterocydoalkan-diyl comprising X4and zero or one ring oxygen atom (notably such heterocycloalkan-diyl represents pyrrolidin-1 ,2-diyl, piperidin-1, 2-diyl, 1 ,3-oxazinan-2,3-diyl, morpholin-3,4-diyl, or oxazolidin-2,3- diyl); wherein said heterocycloalkan-diyl is unsubstituted, or mono- or di-substituted (notably unsubstituted or mono-substituted); wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl), halogen (notably fluoro), (C1-3)alkoxy (notably methoxy), hydroxy, phenyl, and cyano (notably the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl), halogen (notably fluoro), and (C1-3)alkoxy (notably methoxy)); [in particular such Ring E represents pyrrolidin-1, 2-diyl, 3-fluoro-pyrrolidin-1.2-diyl, 4-fl uoro-py rrol id i n- 1 ,2-diyl, 4-methy l-pyrrol id i n-1 ,2-diyl, 4-methoxy-py rrol idi n- 1 ,2-diyl, piperidin-1 , 2-diyl, 1 ,3-oxazinane-2,3-diyl, morpholin-3,4-diyl, or oxazolidine-2,3-diyl]; or o a 6- to 8-membered (notably 6- or 7-membered) saturated spiro, fused, or bridged (notably fused or bridged) bicyclic heterocycloalkan-diyl comprising X4; [in particular such Ring E represents 2- azabicyclo[3.1.0]hexan-2, 3-d iy 1 , 3-azabicyclo[3.1 .0]hexan-2, 3-diy I, or 2-azabicyclo[2.2.1 ]heptan-2.3-diyl];> or CHRC1; wherein R1and RC1together form a ring comprising X4, herein Ring F, wherein said Ring F represents a monocyclic (Cs-ejcycloalkan-diyl (notably cyclopentan-1, 2-diyl) or a monocyclic 5- or 6- membered heterocycloalkan-diyl comprising one ring oxygen atom; andR2represents:> 3-cyano-3,3-dimethylpropyl;> -(CH2)m-(Ring D), wherein m is the integer 0 or 1 (notably 0), and Ring D represents: o a saturated monocyclic (C^cycloalkyl (notably cyclobutyl, cyclopentyl, or cyclohexyl); wherein said (C4-7)cycloalkyl is unsubstituted, mono-, di-, or tri-substituted (especially mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of:■ (C1-3)alkyl (notably methyl); wherein said (C1-3)alkyl independently is unsubstituted or mono- substituted with cyano (notably cyano-methyl);■ halogen (notably fluoro);■ (C1-3)fluoroalkyl;■ C1-3) alkoxy (notably methoxy);■ (C3-4)cycloalkyl (notably cyclopropyl);■ carbamoyl;■ hydroxy;■ cyano; and■ (C2-3)al ky nyl (notably vinyl)[in particular such -(CH2)m-(Ring D) represents 3-cyano-cyclobutyl, 3-(cyanomethyl)-3-methyl- cyclobutyl, 3-cyano-cyclopentyl, 3-hydroxy-cydopentyl, 3-methoxy-cyclopentyl, 3,3-difluoro- cyclopentyl, 3,3-dimethyl-cyclopentyl, 3-cyano-3-methyl-cyclopentyl, 2-cyano-cyclohexyl, 2- hydroxy-cydohexyl, 2-methoxy-cyclohexyl, 3-cyano-cydohexyl, 3-hydroxy-cydohexyl, 3- methoxy-cydohexyl, 4-cyano-cyclohexyl, 4-hydroxy-cydohexyl, 4-(cyanomethyl)-cyclohexyl, 4- methoxy-cydohexyl, 3-cyano-3-methyl-cydohexyl, 3,3-difluoro-cyclohexyl, 4-hydroxy-4-methyl- cyclohexyl, 4-cyano-4-methyl-cyclohexyl (as well as its deuterated isotope 4-cyano-4-(methyl- d3)-cyclohexyl), 4-cyano-4-ethyl-cyclohexyl (as well as its deuterated isotope 4-cyano-4-(ethyl- d5)-cyclohexyl), 4-cyano-4-cyclopropyl-cydohexyl, 4,4-dimethyl-cyclohexyl, 4-fluoro-4-methyl- cyclohexyl, 4,4-difluoro-cyclohexyl, 4,4-difluoro-2-hydroxy-cyclohexyl, or 4-vinyl-cyclohexyl]; a saturated bicyclic ((C5-8)spirocycloalkyl (notably spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, or spiro[2.5]octanyl); wherein said ((C5-8)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen (notably fluoro), cyano, and hydroxy;[in particular such -(CH2)m-(Ring D) represents 4-cyano-spiro[2.2]pentan-1-yl, spiro[2.3]hexan- 5-yl, 1 , 1 -difluoro-spiro[2.3]hexan-5-yl, 1 ,1-difluoro-spiro[2.4]heptan-5-yl, spiro[3.3]heptan-2-yl, 6- hydroxy-spiro[3.3]heptan-2-yl, 6,6-difluoro-spiro[3.3]heptan-2-yl, spiro[2.5]octan-6-yl, 1-cyano- spi ro[2.5]octan-6-y I, 1 , 1 , 2, 2-tetraf luoro-spi ro[2.5]octan-6-y I , or 1 , 1 -d if I uoro-spiro[2.5]octan-6-y I]; a saturated fused or bridged bicyclic (C5.8)cydoalkyl (notably bicyclo[1.1.1]pentanyl, bicydo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, or octahydropentalen-2-yl); wherein said bicyclic ((C5-8)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)fluoroalkyl (notably (Ci)fluoroalkyl; especially trifluoromethyl), halogen (notably fluoro), cyano, and carbamoyl [in particular the substituents are independently selected from the group consisting of: (C1-3)fluoroalkyl (notably (Ci)fluoroalkyl; especially trifluoromethyl), and halogen (notably fluoro)];[in particular such -(CH2)m-(Ring D) represents 5-cyano-octahydropentalen-2-yl, 3- trifluoromethyl-bicyclo[1.1.1]pentan-1-yl, bicyclo[4.1.0]heptan-3-yl, 6,6-difluoro- bicydo[3.1 .0]hexan-3-y I , or 7, 7-d if luoro-bicyclo[4.1.0]heptan-3-y I]; a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from 0, NRN2, S, or SO2 (notably 0, or NRN2); wherein RN2represents (C1-3)alkyl (notably methyl) or cyanomethyl; (notably such heterocycle represents tetrahydropyranyl or piperidinyl); wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted (and in addition substituted with RN2, if present); wherein the substituents are independently selected from thegroup consisting of: (C1-3)alkyl (notably methyl, ethyl, or isopropyl), halogen, (C1-3)fluoroalkyl, and oxo;[in particular such -(CH2)m-Ring D) represents tetrahydropyran-3-yl, (tetrahydropyran-3-yl)- methyl, tetrahydropyran-4-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran-4-yl, 2,6-dimethyl-tetrahydropyran-4-yl, 6,6-dimethyl-tetrahydropyran-3-yl, 2,2,6,6-tetramethyl- tetrahydropyran-4-yl, 1 -methyl-2-oxo-piperidin-4-yl, 1-(cyanomethyl)-pyrrolidin-3-yl, or 1- (cyanomethyl)-3,3-difluoro-pyrrolidin-4-yl]; o a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom [notably such -(CH2)m-(Ring D) represents 2-oxa-spiro[3.5]nonan-7-yl]; o a 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; [notably such -(CH2)m-(Ring D) represents 7-oxa-bicyclo[2.2.1]heptan-2-yl].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 trans- configuration. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art. In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched, especially essentially pure, form. In case 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. Such compound name or generic structure is understood to encompass the compound / generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center. Likewise, in case such stereogenic or asymmetric center is designated as being in (RS)-configuration, this means that such stereogenic or asymmetric center in such compound may be present in (R)-configuration, in (S)-configuration, or in any mixture of epimers with regard to such center. In case two or more such stereogenic or asymmetric centers (in undesignated or designated (RS)-configuration) are present in one molecule, it is understood that the order of absolute configuration does not indicate any defined relative configuration with regard to the two or more centers.In case 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. For example, the compound (12aR*, 15aS*)-11 -(4,4-dif luorocyclohexyl)-3-methyl-6, 7,8, 9, 10, 11 , 13, 14, 15, 15a-decahydrobenzo[b] cyclopenta[e]

[0001] oxa[4]th i a[8]azacyclotrideci n- 12(12aH)-one 16, 16-dioxide encompasses enantiomerically enriched (12aR, 15aS)-11-(4,4-difluorocyclohexyl)-3-methyl-6,7,8,9,10, 11 ,13,14,15,15a-decahydrobenzo[b]cydopenta[e][1] oxa[4]th i a[8] azacyclotrideci n- 12(12aH)-one 16, 16-dioxide, (12aS, 15aR)-11 -(4, 4-d ifl uorocyclohexy l)-3-methyl- 6, 7, 8, 9, 10, 11 , 13, 14, 15, 15a-decahydrobenzo[b]cyclopenta[e]

[0001] oxa[4]thi a[8]azacyclotrideci n- 12(12aH)-one 16,16- dioxide, or any mixture of these stereoisomers of said compound.In drawings of a certain chemical structure (such as in the Table of Examples below), a stereogenic or asymmetric center indicated as “abs” represents said stereogenic or asymmetric center in the respective (R)- or (S)- configuration as drawn. A stereogenic or asymmetric center indicated as “&1” represents said stereogenic or asymmetric center in the respective (RS)-configuration, i.e. comprising the respective (R)- or (S)-configuration or any mixture of epimers at such center.In case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond). A double bond drawn as a crossed double bond :• \ or is understood as encompassing such double bond in enriched (E)- or in enriched(Z)-configuration, or any stereoisomeric mixture comprising such bond in (E)- and (Z)-configuration.The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90: 10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.The present invention also includes isotopically labelled, especially 2H (deuterium, d) labelled compounds of Formula (I) according to embodiments 1) to 22), 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, d) 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, d) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, 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.In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn belowis the 4,4-difluoro-cyclohexyl group.In some instances, 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.Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.Any reference to compounds of Formula (I) according to embodiments 1) to 22) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts depending on the presence of basic and / or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1) to 22), 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 orpreferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.Whenever a substituent is denoted as optional, it is understood that such substituent may be absent, in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.The term “halogen” means fluorine, chlorine, bromine, or iodine; especially fluorine, chlorine, or bromine; preferably fluorine or chlorine.The term “alkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated straight or branched chain hydrocarbon group containing one to six carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (Ci-e)alkyl group contains from one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, and 3,3-dimethyl-butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. An example of RA1representing C1-3) alkyl is methyl. An example of RA2representing (C1-3)alkyl is methyl. An example of RA3representing (C1-3)alkyl is methyl. Examples of (C1-6)alkyl as substituent of linker group L1are methyl, ethyl, n-propyl, and isopropyl. An example of C1-3) alkyl as substituent of L2or L3is methyl. Examples of R1representing (C1-5)alkyl are methyl, isopropyl, sec- butyl, and n-butyl. Examples of R3representing C1-3) alkyl are methyl including methyl-d3. An example of (C1-3)alkyl as substituent of Ring E is methyl. An example of (C1-3)alkyl as substituent of Ring D is methyl, ethyl, or isopropyl (notably methyl). An example of RN1representing (C1-3)alkyl is methyl. An example of RN2representing C1-3) alkyl is methyl.The term “alkoxy”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term “(Cx-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Ci-4)alkoxy group means a group of the formula (Ci-4)alkyl-O- in which the term “(C1-4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy, and tert-butoxy. Preferred is methoxy. An example of RA1representing (C1-3)alkoxy is methoxy. An example of RA3representing (C1-3)alkoxy is methoxy. An example of (C1-3)alkoxy as substituent of Ring E is methoxy. An example of (C1-3)alkoxy as substituent of Ring D is methoxy.The term "fluoroalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “(Cx-y)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a (C1-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2- trifluoroethyl; especially trifluoromethyl. Preferred (C1-3)fluoroalkyl groups are (Ci)fluoroalkyl groups such as difluoromethyl and trifluoromethyl. An example of (C1-3)fluoroalkyl as substituent of Ring D is trifluoromethyl.The term "hydroxy" refers to a group -OH.The term "cyano" refers to a group -ON.The term "oxo" refers to a group =0 which is preferably attached to a chain or ring carbon or sulfur atom as for example in a carbonyl group -(CO)-, or a sulfonyl group -(SO2)-.The term "carbamoyl" refers to a group -C(=O)(NH2).The term “backbone” refers to the atoms forming the shortest continuous chain of atoms between two points of attachment of a fragment or group to the rest of the molecule. Such a backbone may be unsubstited or substituted as explicitly defined; it is understood that all positions having a free valency are saturated with hydrogen where appropriate. Such a backbone may be linear, or may comprise a cyclic moiety, i.e., formed when two or more adjacent backbone atoms are linked together to form a cyclic moiety. In the latter case, the atoms of the cyclic moiety contained in the shortest path between the attachment points of the cyclic moiety to the remaining fragment or group are to be considered as backbone atoms.Examples of backbones as used for linker group L1are *-O-(CH2)2-, *-O-(CH2)3-, -(CH2)4-, *-S-(CH2)3- *-O-(CH2)4- , *-(CH2)-O-(CH2)3- *-(CH2)3-O-(CH2)-, -(CH2)5-, *-NH-(CH2)2-CH=CH-, *-NH-(CH2)4-, *-CH=CH-(CH2)3-, *-O-(CH2)2- CH=CH-, *-O-(CH2)2-O-(CH2)-, and *-O-(CH2)s-; wherein the asterisk indicates the attachment point of linker group L1to Ring A; wherein one or more hydrogen atoms along said backbone may be independently replaced with a substituent, as explicitly defined.Examples of backbones as used for linker group L2are:> *-O-(CH2)-(cyclic moiety)-, *-O-(cyclic moiety)-(CH2)-, *-O-(cydic moiety)-CH=CH-, *-O-(cyclic moiety)- (CH2)2-; wherein notably independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1 ,2-diyl (in particular cyclopropan-1 ,2-diyl, cyclobutan-1 ,2-diyl, cyclopentan-1 ,2- diyl, or cyclohexan-1 ,2-diyl); o phen-1 ,2-diyl; or o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocydoalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho position relative to one another (in particular tetrahyd rofuran-2, 3-diy I or tetrahyd rofuran-3, 4-d iyl); or> *-(cyclic moiety)-(CH2)-, ‘-(cyclic moiety)-(CH2)2-, ‘-(cyclic moiety)-CH=CH-, ‘-(cyclic moiety)-(CH2)s-, *-O- (cydic moiety)-, *-0-(cyclic moiety)-(CH2)-, and *-O-(CH2)-(cyclic moiety)-; wherein notably independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1 ,3-diyl (in particular cyclobutan-1 ,3-diyl, cyclopentan-1, 3-diyl, or cyclohexan- 1 ,3-diyl);o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocydoalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular pyrrolidin-1 ,3-diyl or piperidin-1 ,3-diyl); o 5- or 6-membered heteroaryl-diyl; wherein said heteroary l-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular 1 H-pyrazol- 1 ,3-diyl, pyridin-2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, or 1 ,3,4-oxadiazol-2,5-diyl); wherein the asterisk indicates the attachment point of linker group L2to Ring A; wherein one or more hydrogen atoms along such linker group L2may be independently replaced with a substituent, as explicitly defined.The term “cycloalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms. The term "(Cx-y)cycloalkyl" (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms. For example, a (C3.6)cydoalkyl group contains from three to six carbon atoms. Representative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.The term “(Cx-y)cycloalkyl", "monocyclic (Cx.y)cycloalkyl" or “saturated monocyclic (Cx.y)cycloalkyl”, refers to a saturated monocyclic cycloalkyl group as defined before, containing x to y carbon atoms. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, and cycloheptyl. An example of (C3-4)cycloalkyl representing or as part of R1is cyclopropyl. An example of (C3.6)cycloalkyl as substituent of linker group L1is cydopropyl. Examples of (C^cycloalkyl representing Ring D are cyclobutyl, cydopentyl, and cyclohexyl (notably cyclopentyl and cydohexyl); such Ring D is unsubstituted or substituted as explicitly defined. An example of (C^cycloalkyl as substituent of Ring D is cyclopropyl.The term "mono-unsaturated monocyclic (Cx.y)cydoalkyl” (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 monocyclic hydrocarbon ring containing x to y carbon atoms (i.e., said ring comprises a single unsaturated (double) bond and otherwise contains saturated bonds).The term “(Cx-y)cycloalkan-diyl” or “monocyclic (Cx.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. An example of Ring F representing a monocyclic (Cs-ejcycloalkan-diyl is cydopentan-1 ,2-diyl. An example of (C3-e)cycloalkan-1 , 1-diyl as substituent of linker group L1is cyclopropan-1, 1-diyl. Examples of cyclic moieties of linker group L2representing (C3.6)cycloalkan-diyl are (C3-6)cycloalkan-1,2-diyl (notably cyclopropan-1 , 2-diyl, cyclobutan-1 ,2-diyl, cyclopentan-1 , 2-diyl, and cyclohexan-1,2- diyl) and (C3.6)cycloalkan-l ,3-diyl (notably cyclobutan-1, 3-diyl, cydopentan-1 , 3-diyl, and cyclohexan-1 ,3-diyl); such (C3.6)cycloalkan-diyl is unsubstituted or substituted as explicitly defined.The term "saturated bicyclic (Cx.y)spirocydoalkyl" or "saturated spiro bicyclic (Cx.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. Representative examples of saturatedbicyclic (Cx-y)spirocycloalkyl groups include spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, and spiro[2.5]octanyl. Examples of Ring D representing a saturated spiro bicyclic (Ce- 8)cycloalkyl are spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, and spiro[2.5]octanyl (notably spiro[2.3]hexan-5-yl, spiro[2.4]heptan-5-yl, spiro[3.3]heptan-2-yl, and spiro[2.5]octan-6-yl); such Ring D are unsubstituted or substituted as explicitly defined.The term “saturated fused or bridged bicyclic (Cx-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. Representative examples of saturated fused or bridged bicyclic (Cx-y)cycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.2]octanyl, and octahydropentalenyl. Examples of Ring D representing a saturated fused or bridged bicyclic (C5-8)cycloalkyl are bicyclo[1.1.1]pentanyl, bicydo[3.1.0]hexanyl, and bicyclo[4.1.0]heptanyl, and octahydropentalenyl (notably bicyclo[1.1.1]pentan-1-yl, bicyclo[3.1.0]hexan-3-yl, bicyclo[4.1.0]heptan-3-yl, or octahydropentalen-2-yl); such Ring D are unsubstituted or substituted as explicitly defined.The term "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 / comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term “x- to y-membered heterocycle or “x- to y-membered saturated monocyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. Such heterocycles are unsubstituted or substituted as explicitly defined. Representative examples of 4-membered saturated monocyclic heterocycle groups include oxetanyl, azetidinyl, and thietanyl; representative examples of 5-membered saturated monocyclic heterocycle groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, and thiazolidinyl; representative examples of 6-membered saturated monocyclic heterocycle groups include tetrahydropyranyl, 1,1-dioxide-tetrahydrothiopyranyl, piperidinyl, dioxanyl, morpholinyl, piperazinyl, and hexahydropyrimidinyl; representative examples of 7-membered saturated monocyclic heterocycle groups include oxepanyl. Examples of Ring D representing a 5- or 6-membered saturated monocyclic heterocycle are tetrahydropyranyl or piperidinyl (notably tetrahydropyran-3-yl, tetrahydropyran-4-yl, or piperidin-4-yl); such Ring D are unsubstituted or substituted as explicitly defined.The term "saturated spiro bicyclic heterocycle", 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 comprising one or two ring heteroatoms or heteroatomic groups independently selected from N, 0, S, or S02; 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 / comprises the defined ring heteroatom(s) or heteroatomic groups, and no furtherring heteroatoms or heteroatomic groups). The term “x- to y-membered saturated spiro bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. An example of Ring D representing a 9-membered saturated spiro bicyclic heterocycle is 2-oxa-spiro[3.5]nonanyl (notably 2-oxa- spiro[3.5]nonan-7-yl).The term "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 / comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term “x- to y-membered saturated fused bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms.The term "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 / comprises the defined ring heteroatom(s) or heteroatomic groups, and no further ring heteroatoms or heteroatomic groups). The term “x- to y-membered saturated bridged bicyclic heterocycle” (x and y each being an integer) refers to such a heterocycle containing x to y ring atoms. An example of Ring D representing a 7-membered saturated bridged bicyclic heterocycle comprising one ring oxygen atom is 7-oxabicyclo[2.2.1 ]heptanyl (notably 7-oxabicyclo[2.2.1 ]heptan-2-yl).The term “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 heterocycle as defined before that is bivalently bound; wherein in each instance, the number and nature of ring heteroatoms or heteroatomic groups are explicitly defined. When the cyclic moiety of linker group L2represents a 5- or 6-membered heterocycloalkan-diyl, said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho or in meta position relative to one another; such linkage may be independently via a carbon ring atom or a ring heteroatom of said 5- or 6-membered heterocycloalkan-diyl. Examples of the cyclic moiety of linker group L2representing a 5- or 6-membered heterocycloalkan-diyl are pyrrolidin-1 ,3-diyl, piperidin-1 ,3-diyl, tetrahydrofuran-2,3-diyl, and tetrahydrofuran-3,4-diyl; such cyclic moieties are unsubstituted or substituted as explicitly defined. When X4represents NRN1, and R1and RN1together form a ring comprising X4, herein Ring E, representing a 4- to 6-membered saturated monocyclic heterocycloalkan-diyl comprising X4and zero or one ring oxygen atom, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X4and on the carbon atom attached at the asterix to the group *-CO-N(R2)-; examples are pyrrolidin-1 ,2- diyl, piperidin-1 , 2-diyl, 1 ,3-oxazinan-2,3-diyl, morpholin-3,4-diyl, and oxazolidin-2,3-diyl; such Ring E isunsubstituted or substituted as explicitly defined. In a particular embodiment, the carbon atom of Ring E attached at the asterix to the group *-CO-N(R2)- is not further substituted.The term “x- to y-membered saturated spiro, fused, or bridged bicyclic 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 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, orS. When X4represents NRN1, and R1and RN1together form a ring comprising X4, herein Ring E, representing a 6- to 8-membered (notably 6- or 7-membered) saturated spiro, fused, or bridged bicyclic heterocycloalkan-diyl comprising X4, the points of attachment of said heterocycloalkan-diyl in Formula (I) are on X4and on the carbon atom attached at the asterix to the group *-CO-N(R2)-. An example of Ring E representing a 6- to 8-membered bridged bicyclic heterocycloalkan- diyl is 2-azabicyclo[2.2.1]heptan-2,3-diyl. Examples of Ring E representing a 6- to 8-membered fused bicyclic heterocycloalkan-diyl are 2- azabicyclo[3.1.0]hexan-2,3-diyl and 3-azabicyclo[3.1.0]hexan-2,3-diyl.The term "aryl", used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (especially one to a maximum three), each independently selected from N, 0, or S. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; examples of 6-membered heteroaryl groups are pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and examples of 8- to 10-membered bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, furopyridinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above- mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.The term "heteroaryl-diyl", used alone or in combination, means a heteroaryl as defined before that is bivalently bound. When the cyclic moiety of linker group L2represents a 5- or 6-membered heteroaryl-diyl, said heteroaryl- diyl is linked to the rest of the molecule via two of its ring atoms that are in in meta position relative to one another; such linkage may be independently via a carbon ring atom or a ring heteroatom of said 5- or 6-membered heterocycloalkan-diyl. Examples of a cyclic moiety of linker group L2representing a 5- or 6-membered heteroaryl- diyl are 1 H-pyrazol-1 ,3-diyl, pyridin-2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, and 1 ,3,4-oxadiazol-2,5-diyl; such cyclic moieties are unsubstituted or substituted as explicitly defined.When the fragment formed by:represents a linker group attached to Ring B in beta position relative to X5, as depicted in Formula (IB).When the fragment formed by:(Formula (l-B)), andRing B represents a 5-membered heteroaromatic ring, notably X1represents C or N, X2independently represents C or N, and X5independently represents C or N (in particular C); examples of such bicyclic heteroaryl groups formed by Ring A and Ring B together include 1 H-indol-2,7-diyl, 1 H-pyrrolo[2,3-c]pyridin-2,7-diyl, 1 H-indol-2,4- diyl, 1 H-pyrrolo[3,2-c]pyridin-2,4-diyl, benzofuran-2,7-diyl, furo[2,3-c]pyridin-2,7-diyl, benzofuran-2,4-diyl, furo[3,2- c]pyridin-2,4-diyl, benzo[b]thiophen-2,7-diyl, thieno[2,3-c]pyridin-2,7-diyl, benzo[b]thiophen-2,4-diyl, thieno[3,2- c]pyridin-2,4-diyl, benzo[d]oxazol-2,4-diyl, oxazolo[4,5-c]pyridin-2,4-diyl, benzo[d]oxazol-2,7-diyl, oxazolo[5,4- c]pyridin-2,4-diyl, benzo[d]thiazol-2,4-diyl, thiazolo[4,5-c]pyridin-2,4-diyl, benzo[d]thiazol-2,7-diyl, thiazolo[5,4- c]pyrid i n-2, 4-diyl, benzo[d]i m id azol-2, 7-diy 1 , 1 H-imidazo[4,5-c]pyridin-2,4-diyl, imidazo[1 ,2-a]pyridin-2,8-diyl, imidazo[1 , 2-a]py razi n-2, 8-d iyl, imidazo[1 ,2-a]pyridin-2,5-diyl, imidazo[1 ,2-c]pyrimidin-2,5-diyl, indolizin-2,5-diyl, pyrrolo[1,2-c]pyrimidin-1,6-diyl, 2H-isoindole-2,4-diyl, 2H-pyrrolo[3,4-c]pyridin-2,4-diyl, 2H-indazol-2,4-diyl, 2H- pyrazolo[4,3-c]pyridin-2,4-diyl, 2H-indazol-2,7-diyl, and 2H-pyrazolo[3,4-c]pyridin-2,7-diyl (notably benzo[d]thiazol- 2,4-diyl, imidazo[1 ,2-a]pyridin-2,8-diyl, and 2H-indazol-2,7-diyl); such bicyclic heteroaryl group formed by Ring A and Ring B are unsubstituted or substituted as explicitly defined.When the fragment formed by:(Formula (l-B)), andRing B represents a 6-membered heteroaromatic ring, notably X1represents C or N, X2independently represents C or N, and X5independently represents C or N; examples of such bicyclic heteroaryl groups formed by Ring A and Ring B together include naphthalen-1, 7-diyl, isoquinolin-1 ,7-diyl, 5A4-quinolizin-3,6-diyl, 9A4-pyrido[2, 1 - f]pyrimidin-1, 7-diyl, 5A4-quinolizin-1 ,8-diyl, 5A4-pyrido[1 ,2-a]pyrazin-1 ,8-diyl, quinolin-3,5-diyl, 1 ,6-naphthyridin-3,5- diyl, isoquinolin-3,5-diyl, 2,6-naphthyridin-1 ,7-diyl, quinolin-2,8-diyl, 1 ,7-naphthyridin-2,8-diyl, quinoxalin-2,8-diyl, pyrido[3,4-b]pyrazin-3,5-diyl, cinnolin-3,5-diyl, pyrido[4,3-c]pyridazin-3,5-diyl, quinazolin-2,8-diyl, and pyrido[3,4- d]pyrimidin-2,8-diyl (notably quinolin-2,8-diyl); such bicyclic heteroaryl group formed by Ring A and Ring B are unsubstituted or substituted as explicitly defined.When the fragment formed by:(Formula (l-B)), andRing B represents a 5- to 7-membered heterocyclic ring which is fused with aromatic Ring A (wherein Ring B contains a total of 1 or 2 ring heteroatoms and said heteroatoms are independently selected from N, 0, or S), notably X1represents C, X2independently represents C or N, and X5represents C; examples of fused bicyclic rings formed by Ring A and Ring B include 2, 3-dihydrobenzofuran-2, 7-diyl, 2, 3-dihydrofuro[2,3-c]pyridin-2, 7-diyl, 2,3- dihydrobenzofuran-2,4-diy 1 , 2,3-dihyd rofu ro[3,2-c] py ridin-2, 4-diy I , indolin-2, 7-diyl, 2,3-di hydro-1 H-pyrrolo[2,3- c]pyrid i n-2, 7-diyl, indolin-2, 4-diyl, 2, 3-d i hydro- 1 H-pyrrolo[3,2-c]pyrid i n-2, 4-diyl, 2,3-dihydrobenzo[b]thiophen-2, 7- diyl, 2, 3-dihydrothieno[2,3-c]pyridin-2, 7-diyl, 2, 3-dihydrobenzo[b]thiophen-2, 4-diyl, 2,3-dihydrothieno[3,2-c]pyridin- 2, 4-diyl, 2, 3-d i hydrobenzo[d]thiazol-2, 7-diyl, 1 ,2-dihyd rothiazolo[5, 4-c] pyridi n-2, 4-diyl, 2,3-dihyd robenzo[d]thiazol- 2, 4-diyl, 2, 3-di hyd roth i azolo[4, 5-c]py rid i n-2, 4-diyl, 1 , 2, 3, 4-tetrahydroq ui nol i n-2, 8-d iyl , 1 , 2, 3, 4-tetrahydro- 1 ,7- naphthyrid i n-2, 8-d iyl, 1 , 2, 3, 4-tetrahydroisoq uinoli n-3, 5-d iyl, 1 ,2,3, 4-tetrahyd ro-2, 6-naphthy rid i n-3, 5-d iyl, 1 ,2,3,4- tetrahydroqu i nol i n-3, 5-d iy I, 1 , 2, 3, 4-tetrahydro- 1 , 6-n aphthy rid in-3, 5-diy 1 , 1 , 2, 3, 4-tetrahydroq u i noxal i n-2, 8-diy I,1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-3,5-diyl, 1 ,2,3,4-tetrahydroquinazolin-2,8-diyl, 1,2,3,4-tetrahydropyrido[3,4- d]pyri m idi n-2, 8-diy 1 , 3, 4-di hydro-2 H-benzo[b][ 1 , 4]oxazin-3, 5-d iy I, 3, 4-di hydro-2 H-pyrido[4, 3-b][ 1 , 4]oxazi n-3, 5-d iyl , chroman-2,8-diyl, 3,4-dihyd ro-2H-pyrano[2, 3-c]pyridin-2, 8-diy I , isochroman-3,5-diyl, 3, 4-di hydro-1 H-pyrano[4,3- c]pyridin-3,5-diyl, chroman-3,5-diyl, 3,4-dihydro-2H-pyrano[3,2-c]pyridin-3,5-diyl, and 2, 3,4,5- tetrahydrobenzo[b]oxepi n-2, 9-d iyl (notably 2, 3-d i hyd robenzofu ran-2, 7-d iy 1 , 1 , 2, 3, 4-tetrahyd roqui noli n-2, 8-d iyl , chroman-2,8-diyl, and 2,3,4,5-tetrahydrobenzo[b]oxepin-2,9-diyl); such fused bicyclic ring formed by Ring A and Ring B is unsubstituted or substituted as explicitly defined.Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4.Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus (10% of X) to X plus (10% of X), and preferably to an interval extending from X minus (5% of X) to X plus (5% of X). Likewise, the term “about” placed before a numerical range “X to Y” refers in the current application to an interval extending from X minus (10% of X) to Y plus (10% of Y), and preferably to an interval extending from X minus (5% of X) to Y plus (5% of Y). In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. Besides, the term “room temperature” as used herein refers to a temperature of about 25°C.Further embodiments of the invention are presented hereinafter:2) Another embodiment relates to compounds according to embodiment 1), wherein:Ring A (A in Formula (I)) is a 6-membered aromatic ring, wherein:> RA1represents hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), halogen (notably chloro or fluoro), monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl; [in particular RA1represents hydrogen, (C1-3)alkyl (notably methyl), or (C1-3)alkoxy (notably methoxy), halogen (notably chloro or fluoro)];> X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen (notably fluoro), (C1-3)alkyl (notably methyl), or (C1-3)alkoxy (notably methoxy);> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen (notably fluoro); and> X5represents C;[in particular Ring A represents 6-methyl-pyridin-2,3-diyl, 4-methyl-phen-1 ,2-diyl, 3-fluoro-4-methyl-phen- 1,2-diyl, 5-methyl-pyrazin-2,3-diyl, 3-methoxy-4-methyl-phen-1,2-diyl, 6-fluoro-4-methyl-phen-1 ,2-diyl, 4- chloro-phen-1 ,2-diyl, phen-1,2-diyl, 4-fluoro-phen-1,2-diyl, 3,4-difluoro-phen-1,2-diyl, 4-fluoro-3-methyl- phen-1 ,2-diyl, 3-fluoro-4-methoxy-phen-1 ,2-diyl, or 3-fluoro-4-methyl-phen-1 ,2-diyl];and L represents:> linker group L1, wherein the backbone of said linker group L1is linear and consists of a total of 3 to 6 (notably 4 or 5) backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 (notably 3 to 5) carbon atoms and 0 to 2 (notably 0 or 1) heteroatoms independently selected from 0, N or S; wherein said backbone is saturated or partially unsaturated (notably is saturated or mono- unsaturated); wherein said backbone is unsubstituted, or mono-, di- or tri-substituted (notably unsubstituted, or mono- or di-substituted; especially mono- or di-substituted); wherein the substituents are independently selected from the group consisting of:■ (C1-6)alkyl (notably methyl, ethyl, n-propyl, or isopropyl; especially methyl);■ (C3-6)cycloalkan-1,1-diyl (notably cyclopropan-1,1 -diyl);■ (C3.6)cycloalkyl (notably cyclopropyl);■ hydroxy;■ halogen (notably fluoro); and, in addition,■ C1-3) fluoroalkyl (notably trifluoromethyl);> or linker group L2, wherein the backbone of said linker group L2consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 (notably 1) heteroatom independently selected from 0, N or S (notably 0 or N); wherein said backbone is saturated or partially unsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6-membered saturated, partially unsaturated or aromatic cyclic moiety comprising a total of 0 to 3 heteroatoms independently selected from 0, N or S; wherein notably said cyclic moiety represents:■ (C3.6)cycloalkan-diyl (notably (C3-6))ycloalkan-1 ,2-diyl or (C3-6)cycloalkan-1,3-diyl; in particular cyclopropan-1 ,2-diyl, cyclobutan-1, 2-diyl, cyclopentan-1 , 2-diyl, cyclohexan-1 ,2- diyl, cyclobutan-1 ,3-diyl, cyclopentan-1, 3-diyl, or cyclohexan-1 , 3-diyl);■ phen-diyl (notably phen-1, 2-diyl);■ 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho or in meta position relative to one another (in particular such 5- or 6-membered heterocycloalkan-diyl represents pyrrolidin-1 , 3-diyl, piperidin-1, 3-diyl, tetrahydrofuran-2, 3-diyl, or tetrahydrofuran-3,4-diyl); or■ 5- or 6-membered heteroaryl-diyl wherein said heteroaryl-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular such 5- or 6-membered heteroaryl-diyl represents 1 H-pyrazol-1 , 3-diyl, pyridin-2,6- diyl, 1 ,2,4-oxadiazol-3,5-diyl, or 1 ,3,4-oxadiazol-2,5-diyl); wherein L2is unsubstituted, or mono- or di-substituted (notably unsubstituted or mono-substituted); wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl) and halogen (notably chloro);[in particular said cyclic moiety represents cyclopropan-1 ,2-diyl, cydobutan-1 ,2-diyl, cyclopentan-1 ,2- diyl, cydohexan-1 ,2-diyl, cyclobutan-1 , 3-diyl, cyclopentan-1, 3-diyl, cydohexan-1 ,3-diyl, pyrrolidin- 1 , 3-diyl, piperidin-1 , 3-diyl, 1 H-pyrazol-1 , 3-diyl, tetrahydrofuran-2, 3-diyl, tetrahydrofuran-3,4-diyl, pyridin-2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, 1 ,3,4-oxadiazol-2,5-diyl, phen-1 ,2-diyl, or 4-chloro-1 H- pyrazol-1 , 3-diyl],3) Another embodiment relates to compounds according to embodiment 2), wherein Ring A is a 6-membered aromatic ring, wherein:> RA1represents independently hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), or halogen (notably chloro or fluoro);> X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen (notably fluoro), (C1-3)alkyl (notably methyl), or (C1-3)alkoxy (notably methoxy);> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen (notably fluoro); and> X5represents C.4) Another embodiment relates to compounds according to embodiment 2), wherein Ring A is a 6-membered aromatic ring, wherein:> RA1represents independently hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), or halogen (notably fluoro);> X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen (notably fluoro), or C1-3) alkyl (notably methyl);> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen (notably fluoro); and> X5represents C;[in particular Ring A represents 6-methyl-pyridin-2, 3-diyl, 4-methyl-phen-1 ,2-diyl, 3-fluoro-4-methyl-phen-1 ,2-diyl, 5-methyl-pyrazin-2, 3-diyl, 6-fluoro-4-methyl-phen-1,2-diyl, 4-chloro-phen-1 ,2-diyl, phen-1 ,2-diyl, 4-fluoro-phen-1 ,2- diyl, 3,4-difluoro-phen-1,2-diyl, 4-fluoro-3-methyl-phen-1 ,2-diyl, 3-fluoro-4-methoxy-phen-1 ,2-diyl, or 3-fluoro-4- methyl-phen-1 ,2-diyl],5) Another embodiment relates to compounds according to any one of embodiments 2) to 4), wherein❖ L represents linker group L1and the backbone of linker group L1is selected from the group consisting of: *-O-(CH2)2-, *-O-(CH2)3-, -(CH2)4-, *-S-(CH2)3-, *-O-(CH2)4-, *-(CH2)-O-(CH2)3-, *-(CH2)3-O-(CH2)-, -(CH2)5- , *-NH-(CH2)2-CH=CH-, *-NH-(CH2)4-, *-CH=CH-(CH2)3-, *-O-(CH2)2-CH=CH-, *-O-(CH2)2-O-(CH2)-, and *-O-(CH2)5-, and, in addition, *-O-(CH2)2-NH-(CH2)-, (notably from the group consisting of: *-O-(CH2)3-, *- S-(CH2)3-, *-O-(CH2)4-, -(CH2)5-, *-O-(CH2)2-O-(CH2)-, *-NH-(CH2)2-CH=CH-, and *-NH-(CH2)4-, and, in addition, *-O-(CH2)2-NH-(CH2)-), wherein the asterisks indicate the attachment point of linker group L1to Ring A; wherein said backbone is unsubstituted, or mono- or di-substituted (notably mono- or di- substituted); wherein the substituents are independently selected from the group consisting of:• (Ci-e)alkyl (notably methyl, ethyl, n-propyl, or isopropyl; especially methyl or ethyl);• (C3.6)cycloalkan-l , 1 -diyl (notably cyclopropan-1 , 1 -diyl, i.e. two of said substituents together with the backbone carbon atom to which they are attached form said (C3-6)cycloalkan-1, 1 -diyl, notably cyclopropan-1 , 1 -diyl group);• (C3.6)cycloalkyl (notably cyclopropyl);• hydroxy; and• halogen (notably fluoro); and, in addition,• (C1-3)fluoroalkyl (notably trifluoromethyl or 2,2,2-trifl uoroethyl); or❖ L represents linker group L2and the backbone of linker group L2is selected from the group consisting of:> *-O-(CH2)-(cyclic moiety)-, *-O-(cyclic moiety)-(CH2)-, *-O-(cyclic moiety)-CH=CH-, *-O-(cydic moiety)-(C H 2)2-; wherein independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1,2-diyl (in particular cyclopropan-1, 2-diyl, cyclobutan-1 ,2-diyl, cyclopentan-1 ,2-diyl, or cyclohexan-1, 2-diyl); o phen-1 , 2-diyl; or o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho position relative to one another (in particular tetrahydrofuran-2, 3-d iyl or tetrahyd rofuran-3, 4-diy I); or> ‘-(cyclic moiety)-(CH2)-, ‘-(cyclic moiety)-(CH2)2- ‘-(cyclic moiety)-CH=CH-, ‘-(cyclic moiety)-(CH2)3-, ‘-□-(cyclic moiety)-, *-O-(cyclic moiety)-(CH2)-, and *-O-(CH2)-(cyclic moiety)-; wherein independently the cyclic moiety of such linker group L2represents: o (C3.6)cycloalkan-l , 3-diyl (in particular cyclobutan-1 , 3-diyl, cyclopentan-1, 3-diyl, or cyclohexan-1 , 3-diyl); o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular pyrrolidin-1 , 3-diyl or piperidin-1, 3-diyl); o 5- or 6-membered heteroaryl-diyl; wherein said heteroaryl-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position (also referred to as 1, 3-diyl position) relative to one another (in particular 1 / 7-pyrazol-1, 3-diyl, pyridin-2,6-diyl, 1 ,2,4- oxadiazol-3,5-diyl, or 1 ,3,4-oxadiazol-2,5-diyl); wherein the asterisks indicate the attachment point of linker group L2to Ring A; wherein said L2is unsubstituted, or mono- or di-substituted (notably unsubstituted or mono-substituted); wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl) and halogen (notably chloro).6) Another embodiment relates to compounds according to any one of embodiments 2) to 4), wherein in case L represents linker group L1; said linker group L1independently is:“-O-CH(CH3)-CH2-; “-O-CH2-CH2-CH2-; “-O-CH(CH3)-CH2-CH2-; “-O-cyclopropan-1 ,1-diyl-CH2-CH2-; - CH2-CH2-CH2-CH2-; “-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; “-CH=CH-CH2-CH2-CH2-; “-O- CH2-CH2-CH2-CH2-; “-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; “-O-CH(n-propyl)-CH2-CH2-CH2-; **-O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2- CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2- CH2-; **-O-CH2-CH2-C(CH3)2-CH2-; **-O-CH2-CH2-cyclopropan-1 ,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2-CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2- CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O-CH(CH3)-CH2-O-CH2-; **-NH<WCH2-CH2-CH2-; **-N(CH3)- CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH=CH-; **-NH-CH(CH3)-CH2- CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; or, in addition to the above-listed, **-O-CH(ethyl)-CH2-O-CH2-; **-O-CH(CH3)-CH2-CH(CH3)-CH2-; **-O- CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)-CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2-CH2-CH2-; **- O-CH2-CH2-CH(CF3)-CH2-;**-O-CH2-CH2-N(2,2,2-trifluoroethyl)-CH2-; or **-O-CH2-CH2-CH=CH-; wherein in subembodiment L represents linker group L1; wherein especially linker group L1is independently selected from:“-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-O-CH2-CH2- CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2-CH2-CH2-; **-O- CH(isopropyl)-CH2-CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2- CH(ethyl)-CH2-; “-O-CH2-CF2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH- CH(CH3)-CH2-CH=CH-; or **-NH-CH(CH3)-CH2-CH2-CH2-; or, in addition to the above-listed, **-O-CH(CH3)-CH2-O-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O-CH(CH3)-CH2- CH(CH3)-CH2-; **-O-CH(CF3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH(CF3)-CH2-; wherein the double asterisks indicate the attachment point of linker group L1to Ring A.7) Another embodiment relates to compounds according to any one of embodiments 2) to 4), wherein L represents linker group L1; wherein linker group L1is selected from:wherein the double asterisks indicate the attachment point of linker group L1to Ring A.8) Another embodiment relates to compounds according to any one of embodiments 2) to 4), wherein L represents linker group L2; wherein linker group L2is selected from:> *-O-(CH2)-(cyclic moiety)-, *-O-(cydic moiety)-(CH2)-, *-O-(cyclic moiety)-CH=CH-, or *-O-(cyclic moiety)- (CH2)2-; wherein notably independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1 ,2-diyl (in particular cyclopropan-1 ,2-diyl, cyclobutan-1,2-diyl, cyclopentan-1 ,2- diyl, or cyclohexan-1 ,2-diyl); o phen-1 ,2-diyl; or o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocydoalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho position relative to one another (in particular tetrahyd rofuran-2, 3-diy I or tetrahyd rofuran-3, 4-d iyl); or> *-(cyclic moiety)-(CH2)-, ‘-(cyclic moiety)-(CH2)2-, ‘-(cyclic moiety)-CH=CH-, ‘-(cyclic moiety)-(CH2)3-, *-O- (cydic moiety)-, *-O-(cyclic moiety)-(CH2)-, or *-0-(CH2)-(cyclic moiety)-; wherein notably independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1 ,3-diyl (in particular cyclobutan-1 ,3-diyl, cyclopentan-1, 3-diyl, or cyclohexan-1.3-diyl); o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular pyrrolidin-1 , 3-diyl or piperidin-1, 3-diyl); or o 5- or 6-membered heteroaryl-diyl; wherein said heteroaryl-diy I is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another (in particular 1 H-pyrazol-1.3-diyl, pyridin-2,6-diyl, 1 ,2,4-oxadiazol-3,5-diyl, or 1 ,3,4-oxadiazol-2,5-diyl); wherein said linker group L2is unsubstituted or mono-substituted with halogen (notably chloro); wherein the asterisks indicate the attachment point of linker group L2to Ring A.9) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein in case L represents linker group L2; said linker group L2independently is:**-(pyrrolidin-1*,3-diyl)-CH2-; “-(piperidin-1 *,3-diyl)-CH2-; **-O-CH2-(cydopropan-1,2-diyl)-; **-O-CH2- (cyclobutan-1 ,2-diyl)-; **-O-(cyclopentan-1 ,2-diyl)-C H2-; **-O-(cyclohexan-1 ,2-diyl)-C H2-; “-O-(cydohexan-1 ,3-diyl)-; **-O-(cyclohexan-1 ,3-diyl)-CH2-; **-(py rrolidin- 1 *, 3-d iy l)-C H2-CH2-; “-O- (cyclopentan-1,2-diyl)-CH=CH-; **-O-(cydopentan-1,3-diyl)-CH2-; **-O-(cydopentan-1,2-diyl)-CH2-CH2-;**-O-CH2-(cyclobutan-1,3-diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1,3*-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1 , 2-d iy l)-C H2-C H2-; **-O-CH2-CH2- (cyclopropan-1 ,2-diyl)-; **-O-([1 ,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin- 2,6-diyl)-CH2-CH2-; **-([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **- O-(tetrahydrofuran-2,4*-diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1 ,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1 ,3-diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; or **-O-(cyclohexan-1,2-diyl)-CH2- CH2-; or, in addition to the above-listed, **-O-CH2-(cyclopropan-1,2-diyl)-CH2-;**-O-CH(CH3)-CH2-(cyclopropan- 1 ,2-diyl)-; **-(pyrazol-1,3*-diyl)-CH2-CH2-; or **-O-(cyclopentan-1,2-diyl)-O-CH2-; wherein in a subembodiment L represents linker group L2; wherein the double asterisks indicate the attachment point of linker group L2to Ring A; and, where applicable, the single asterisks indicate the attachment point of the linker oxygen atom which is attached to Ring A, or of Ring A, as the case may be.10) Another embodiment relates to compounds according to any one of embodiments 2) to 4), wherein L represents linker group L2; wherein linker group L2is selected from:Z£wherein the double asterisk indicates the attachment point of linker group L2to Ring A.11) Another embodiment relates to compounds according to embodiment 1), wherein Ring A and L together represent:Formula (l-B).12) Another embodiment relates to compounds according to embodiment 11), wherein the fragment:wherein in the above groups RA1independently is as defined in embodiment 1).13) Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein X3represents SO2 or S(O)(NR3), wherein R3represents hydrogen or (C1-3)alkyl (notably methyl including methyl-c / 3).14) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein X4represents CHRC1, and R1and RC1together form a ring comprising X4, herein Ring F, wherein Ring F represents a monocyclic (Cs-ejcycloalkan-diyl (notably cyclopentan-1 , 2-diyl).In a sub-embodiment of embodiment 14), X3notably represents SO2, S(=O)(=NH), or S(=O)(=N(CH3)); especially SO2or S(=O)(=N(CH3)).15) Another embodiment relates to compounds according to embodiment 14), wherein the substituents -X3-(Ring A) and -C(=O)NR2of Ring F are in relative trans configuration.When X4represents CH, the compounds of Formula (I) contain at least two stereogenic centers which are situated at the two carbon atoms of Ring F that link Ring F to -X3-(Ring A) and to -C(=O)NR2. Thus, according to this embodiment, a compound of Formula (I) represents either a compound of Formula (I l-F), or a compound of Formulain a particular embodiment, the compounds of Formula (I) are also compounds of Formula (lll-F).16) Another embodiment relates to compounds according to any one of embodiments 1) to 13), wherein X4represents NRN1, and R1and RN1together form a ring comprising X4, herein Ring E, wherein said Ring E is, mutatis mutandis, as defined in embodiment 1), especially Ring E is pyrrolidin-1 , 2-diyl.17) Another embodiment relates to compounds according to embodiment 16), wherein the compounds of Formula (I) represents a compound of Formula (ll-E):In a sub-embodiment of embodiment of embodiment 17), the compounds of Formula (I) represents a compound of Formula (ll-E) and:• Ring A represents a 6-membered aromatic ring as defined in embodiment 4);• L represents linker group L1; notably L represents linker group L1as defined in any one of embodiments 5) to 7);• X3is as defined in embodiment 13); and• R2is as defined in embodiment 21 ).18) Another embodiment relates to compounds according to embodiment 16) or 17), wherein Ring E represents:• a 5- or 6-membered saturated monocyclic heterocydoalkan-diyl comprising X4and zero or one ring oxygen atom (notably pyrrolidin-1 ,2-diyl, piperidin-1 ,2-diyl, 1 ,3-oxazinan-2,3-diyl, morpholin-3,4-diyl, or oxazolidin- 2,3-diyl); wherein said heterocycloalkan-diyl is unsubstituted or mono-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl), halogen (notably fluoro), and (C1-3)alkoxy (notably methoxy); [in particular such Ring E represents pyrrolidin-1 ,2- diyl, 3-fluoro-pyrrolidin-1, 2-diyl, 4-fluoro-pyrrolidin-1, 2-diyl, 4-methyl-pyrrolidin-1 ,2-diyl, 4-methoxy- pyrrolidin-1 ,2-diyl, piperidin-1 , 2-diyl, 1 ,3-oxazinane-2,3-diyl, morpholin-3,4-diyl, or oxazolidine-2,3-diyl]; or• a 6- or 7-membered saturated fused or bridged bicyclic heterocycloalkan-diyl comprising X4; [in particular such Ring E represents 2-azabicydo[3.1.0]hexan-2,3-diyl, 3-azabicyclo[3.1.0]hexan-2,3-diyl, or 2- azabicydo[2.2.1]heptan-2,3-diyl],19) Another embodiment relates to compounds according to embodiment 16) or 17), wherein said Ring E represents:• a 5- or 6-membered saturated monocyclic heterocycloalkan-diyl comprising X4and zero or one ring oxygen atom (notably pyrrolidin-1, 2-diyl, piperidin-1 , 2-diyl, 1 ,3-oxazinan-2,3-diyl, morpholin-3,4-diyl, or oxazolidin- 2,3-diyl); wherein said heterocycloalkan-diyl unsubstituted or mono-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl), halogen (notably fluoro), and C1-3) alkoxy (notably methoxy); [in particular such Ring E represents pyrrolidin-1, 2-diyl, 4- fluoro-pyrrolidin-1 , 2-diyl, 4-methyl-pyrrolidin-1, 2-diyl, 4-methoxy-pyrrolidin-1 , 2-diyl, piperidin-1 , 2-diyl, 1 ,3- oxazinane-2,3-diyl, morpholin-3,4-diyl, or oxazolid i ne-2,3-diyl]; ora 6-membered saturated fused bicyclic heterocydoalkan-diyl comprising X4; [in particular such Ring E represents 2-azabicyclo[3.1 .0]hexan-2,3-diyl or 3-azabicydo[3.1 ,0]hexan-2,3-diyl].20) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R2represents:> 3-cyano-3,3-dimethylpropyl;> -(CH2)m-(Ring D), wherein m is the integer 0 or 1 (notably 0), and Ring D represents: o a saturated monocyclic (C^cycloalkyl (notably cyclobutyl, cyclopentyl, or cyclohexyl); wherein said (C4-7cycloalkyl is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of:■ (C1-3)alkyl (notably methyl); wherein said (C1-3)alkyl is unsubstituted or mono-substituted with cyano (notably cyano-methyl);■ halogen (notably fluoro);■ C1-3) alkoxy (notably methoxy);■ (C3-4)cycloalkyl (notably cydopropyl);■ hydroxy; and■ cyano;[in particular such -(CH2)m-(Ring D) represents 3-cyano-cyclobutyl, 3-(cyanomethyl)-3-methyl- cyclobutyl, (3,3-difluorocyclobutyl)-methyl, 2-hydroxy-cydopentyl, 2-methoxy-cyclopentyl, 3- cyano-cydopentyl, 3-hydroxy-cydopentyl, 3-methoxy-cyclopentyl, 3,3-difluoro-cyclopentyl, 2- cyano-cyclohexyl, 2-hydroxy-cyclohexyl, 2-methoxy-cydohexyl, 3-cyano-cyclohexyl, 3-hydroxy- cyclohexyl, 3-methoxy-cyclohexyl, 4-cyano-cyclohexyl, 4-hydroxy-cydohexyl, 4-(cyanomethyl)- cyclohexyl, 4-methoxy-cyclohexyl, 2-hydroxy-2-methyl-cyclohexyl, 3-cyano-3-methyl-cyclohexyl, 3,3-difluoro-cyclohexyl, 4-hydroxy-4-methyl-cyclohexyl, 4-cydopropyl-4-hydroxy-cyclohexyl, 4- cyano-4-methyl-cyclohexyl, 4-cyano-4-cyclopropyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 4-fluoro- 4-methyl-cyclohexyl, 4, 4-d ifl uoro-cyclohexyl, 4,4-difluoro-2-hydroxy-cyclohexyl, or 4,4-difl uoro-2- methoxy-cydohexyl]; o a saturated bicyclic ((C5-8)spirocycloalkyl (notably spiro[2.2]pentanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, or spiro[2.5]octanyl); wherein said ((C5-8)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen (notably fluoro), cyano, and hydroxy; [in particular such -(CH2)m-(Ring D) represents 4-cyano-spiro[2.2]pentan-1-yl, spiro[2.3]hexan-5-yl, 1,1- difluoro-spiro[2.3]hexan-5-yl, 1 ,1-difluoro-spiro[2.4]heptan-5-yl, spiro[3.3]heptan-2-yl, 6-hydroxy- spiro[3.3]heptan-2-yl, 6,6-difluoro-spiro[3.3]heptan-2-yl, spiro[2.5]octan-6-yl, 1-cyano- spi ro[2.5]octan-6-y I, 1 , 1 , 2, 2-tetraf luoro-spi ro[2.5]octan-6-y I , or 1 , 1 -d if I uoro-spiro[2.5]octan-6-y I]; o a saturated fused or bridged bicyclic ((C5-8)cycloalkyl (notably bicyclo[1.1.1]pentanyl, bicydo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, or octahydropentalen-2-yl); wherein said bicyclic((C5-8)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)fluoroalkyl (notably (Ci)fluoroalkyl; especially trifluoromethyl), halogen (notably fluoro), and cyano; [in particular such -(CH2)m-(Ring D) represents 5-cyano-octahydropentalen-2-yl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-yl, 6,6- dif I uoro-bicyclo[3.1 .0]hexan-3-y I , bicyclo[4.1 .0]heptan-3-y I , or 7, 7-d if I uoro-bicyclo[4.1.0]heptan- 3-yl]; o a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from 0, NRN2, or SO2; wherein RN2represents (C1-3)alkyl (notably methyl); (notably such heterocycle represents tetrahydropyranyl or piperidinyl); wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl (notably methyl, ethyl, or isopropyl) and oxo; [in particular such -(CH2)m-(Ring D) represents tetrahydropyran-3-yl, (tetrahydropyran-3-yl)-methyl, tetrahydropyran-4-yl, 2-isopropyl-tetrahydropyran-4-yl, 2-methyl-tetrahydropyran-4-yl, 2,2- dimethyl-tetrahydropyran-4-yl, 2,2-diethyl-tetrahydropyran-4-yl, 2,6-dimethyl-tetrahydropyran-4- yl, 6,6-dimethyl-tetrahydropyran-3-yl, 2,2,6,6-tetramethyl-tetrahydropyran-4-yl, or 1-methyl-2- oxo-piperidin-4-yl]; o a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom [notably such -(CH2)m-(Ring D) represents 2-oxa-spiro[3.5]nonan-7-yl]; or o a 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; [notably such -(CH2)m-(Ring D) represents 7-oxa-bicyclo[2.2.1]heptan-2-yl]; .21) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R2represents:> 3-cyano-3,3-dimethylpropyl;> Ring D, wherein Ring D represents: o a saturated monocyclic (C^cydoalkyl (notably cyclopentyl or cyclohexyl); wherein said (C4-7)cycloalkyl is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of:■ (C1-3)alkyl (notably methyl); wherein said (C1-3)alkyl is unsubstituted or mono-substituted with cyano (notably cyano-methyl);■ halogen (notably fluoro);■ (C1-3)alkoxy (notably methoxy);■ (C3-4)cycloalkyl (notably cyclopropyl);■ hydroxy; and■ cyano;[in particular such Ring D represents 3-(cyanomethy l)-3-methy l-cyclobuty 1 , 3-cyano-cyclopentyl, 3,3-difluoro-cyclopentyl, 2-cyano-cyclohexyl, 2-hydroxy-cydohexyl, 2-methoxy-cyclohexyl, 3-cyano-cyclohexyl, 3-hydroxy-cyclohexyl, 3-methoxy-cydohexyl, 4-cyano-cyclohexyl, 4-hydroxy- cyclohexyl, 4-(cyanomethyl)-cydohexyl, 3-cyano-3-methyl-cydohexyl, 3,3-difluoro-cyclohexyl, 4- cyano-4-methyl-cydohexyl, 4-cyano-4-cyclopropyl-cyclohexyl, 4,4-dimethyl-cyclohexyl, 4-fluoro- 4-methyl-cydohexyl, 4,4-difluoro-cyclohexyl, or 4,4-difluoro-2-hydroxy-cyclohexyl]; o a saturated bicyclic (C5-8)spirocycloalkyl (notably spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, or spiro[2.5]octanyl); wherein said (C5-8)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen (notably fluoro) and cyano; [in particular such Ring D represents 1 , 1 -d if I uoro-spi ro[2.3]hexan-5-yl , 1 , 1 -difluoro-spi ro[2.4]heptan-5-y I, spiro[3.3]heptan-2-y I , spiro[2.5]octan-6-yl, 1-cyano-spiro[2.5]octan-6-yl, 1 ,1,2,2-tetrafluoro-spiro[2.5]octan-6-yl, or 1 ,1- d if I uoro-spi ro[2.5]octan-6-y I ] ; o a saturated fused or bridged bicyclic (C5-8)cycloalkyl (notably bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, or octahydropentalen-2-yl); wherein said bicyclic ( (C5-8)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: halogen (notably fluoro) and cyano; [in particular such Ring D represents 5-cyano-octahydropentalen-2-yl, 6,6-difluoro-bicyclo[3.1 ,0]hexan-3-yl, bicydo[4.1.0]heptan-3-yl, or 7, 7-dif I uoro-bicyclo[4.1 ,0]heptan-3-yl]; o a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from 0 or SO2 (notably such heterocycle represents tetrahydropyranyl or piperidinyl); wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently (C1-3)alkyl (notably methyl or ethyl); [in particular such Ring D represents tetrahydropyran-4-yl, 2-methyl-tetrahydropyran-4-yl, 2,2-dimethyl-tetrahydropyran-4- yl, 2,2-diethyl-tetrahydropyran-4-yl, 2,6-dimethyl-tetrahydropyran-4-yl, 6,6-dimethyl- tetrahydropyran-3-yl, or 2,2,6, 6-tetramethyl-tetrahydropyran-4-yl],22) Another aspect of the invention relates to compounds of Formula (IV)wherein the fragment> RA1independently represents hydrogen, (C1-3)alkyl (notably methyl), (C1-3)alkoxy (notably methoxy), or halogen (notably chloro or fluoro); and> RA3, if present, independently represents hydrogen, halogen (notably fluoro), or (C1-3)alkyl (notably methyl);[in particular said fragment represents 6-methyl-pyridin-2,3-diyl, 4-methyl-phen-1,2-diyl, 3-fluoro-4-methyl- phen-1 ,2-diyl, or 5-methy l-pyrazi n-2, 3-d iyl];L represents:• linker group L1wherein such linker group L1independently is:**-O-CH(CH3)-CH2-; **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-O-cyclopropan-1,1-diyl-CH2-CH2-; -CH2- CH2-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-CH=CH-CH2-CH2-CH2-; **-O-CH2-CH2- CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2-CH2-CH2-; **- O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O- CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2-CH2-; **-O-CH2-CH2-C(CH3)2- CH2-; **-O-CH2-CH2-cyclopropan-1,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2- CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2-CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O- CH(CH3)-CH2-O-CH2-; **-NH-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2- CH=CH-; **-NH-CH(CH3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O- CH2-CF2-CH2-CH2-; **-O-CH(CH3)-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)- CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2-CH2- CH2-; **-O-CH2-CH2-CH(CF3)-CH2-; or **-O-CH2-CH2- N(2,2,2-trifluoroethyl)-CH2-;[especially such linker group L1is **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **- O-CH2-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2- CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O- CH2-CF2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-O-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O- CH(CH3)-CH2-CH(CH3)-CH2-; **-O-CH(CF3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH(CF3)-CH2-]; wherein the double asterisks indicate the attachment point of said linker group L1to Ring A; or• linker group L2; wherein such linker group L2independently is:**-(py rrol id i n-1 *,3-diy l)-C H2-; **-(pi peridi n-1 *,3-diyl)-C H2-; **-O-CH2-(cyclopropan-1 ,2-diyl)-; **-O-CH2- (cyclobutan-1 ,2-diyl)-; **-O-(cyclopentan-1,2-diyl)-CH2-; **-O-(cyclohexan-1 ,2-diyl)-CH2-; **-O-(cyclohexan- 1 ,3-diyl)-; **-O-(cyclohexan-1,3-diyl)-CH2-; **-(pyrrolidin-1 *,3-diyl)-CH2-CH2-; **-O-(cyclopentan-1,2-diyl)- CH=CH-; **-O-(cyclopentan-1,3-diyl)-CH2-; **-O-(cyclopentan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclobutan-1,3- diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1 , 3*-d iyl)-CH2-C H2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1,2-diyl)-CH2-CH2-; **-O-CH2-CH2-(cyclopropan-1,2- diyl)-; **-O-([1,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin-2,6-diyl)-CH2-CH2-; **- ([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,4*- diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1,3- diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclopropan-1,2- diyl)-CH2-; **-O-CH(CH3)-CH2-(cyclopropan-1,2-diyl)-; **-(pyrazol-1,3*-diyl)-CH2-CH2-; or **-O-(cyclopentan-1.2-diyl)-O-CH2-; [especially **-O-(cyclopentan-1,2-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-; **-O- (cyclohexan-1 ,3-diyl)-; **-O-(cyclohexan-1,3-diyl)-CH2-; **-O-(cyclopentan-1,3-diyl)-CH2-; **-O-(cyclopentan-1.2-d iy l)-CH2-C H2-; **-O-CH2-CH2-(cyclopropan-1 ,2-diyl)-; **-O-CH(CH3)-CH2-(cyclopropan-1 ,2-diyl)-; **-O- (tetrahydrofuran-2,4*-diyl)-CH2-; **-(pyrrolidin-1*,3-diyl)-CH2-CH2-; or **-O-(cyclopentan-1,2-diyl)-O-CH2-]; wherein the double asterisks indicate the attachment point of linker group L2to Ring A; and, where applicable, the single asterisks indicate the attachment point of the linker oxygen atom which is attached to Ring A, or of Ring A, as the case may be;X3represents SO2 or S(O)(NR3), wherein R3represents hydrogen or methyl (including methyl-d3), [in particular X3represents SO2, S(=O)(=NH), S(=O)(=N(CH3)), or S(=O)(=N(CD3))];X4represents N or CH; andR2represents:> cyclopentyl or cyclohexyl; wherein said cyclopentyl or cyclohexyl independently is mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-3)alkyl (notably methyl), halogen (notably fluoro), and cyano;[in particular 3-cyano-cydopentyl, 3,3-difluoro-cyclopentyl, 3,3-dimethyl-cyclopentyl, 3-cyano-3-methyl- cydopentyl, 3-cyano-cydohexyl, 4-cyano-cydohexyl, 3-cyano-3-methyl-cydohexyl, 3,3-difluoro-cyclohexyl, 4- cyano-4-methyl-cyclohexyl (as well as its deuterated isotope 4-cyano-4-(methyl-d3)-cyclohexyl), 4-cyano-4- ethyl-cyclohexyl (as well as its deuterated isotope 4-cyano-4-(ethyl-d5)-cyclohexyl), 4,4-dimethyl-cyclohexyl, 4-fluoro-4-methyl-cyclohexyl, 4,4-difluoro-cyclohexyl]; or> a saturated bicyclic (C6-8)spirocycloalkyl (notably spiro[2.3]hexanyl, or spiro[2.5]octanyl); wherein said (C6-8)spirocycloalkyl is unsubstituted, or di-substituted with fluoro; [in particular 1 , 1 -difluoro-spiro[2.3]hexan-5- yl, 1 ,1-difluoro-spiro[2.4]heptan-5-yl, 6,6-difluoro-spiro[3.3]heptan-2-yl, or 1 ,1-difluoro-spiro[2.5]octan-6-yl],23) Another embodiment relates to compounds according to embodiment 1) which are selected from the following example compounds (wherein the chemical name of the compound is as in the experimental part, and the structure is as in the Table of Examples herein below):1.1 ; 1.2; 1.3; 1.4; 1.6; 1.5; 1.7; 1.8; 1.9; 1.10; 1.11 ; 1.12; 1.13; 1.14; 1.15; 1.18; 1.19; 1.20; 1.21; 1.22; 1.23; 1.24;1.25; 1.26; 1.27; 1.28; 1.29; 1.30; 1.31 ; 1.32; 1.33; 1.34; 1.35; 1.36; 1.37; 1.38; 1.39; 1.40; 1.41 ; 1.42; 1.43; 1.44;1.45; 1.46; 1.48; 1.49; 1.50; 1.51; 1.52; 1.53; 1.54; 1.55; 1.56; 1.57; 1.58; 1.59; 1.60; 1.61; 1.62; 1.63; 1.64; 1.65;1.66; 1.67; 1.68; 1.69; 1.70; 1.71; 1.72; 1.73; 1.74; 1.75; 1.76; 1.77; 1.78; 3.1 ; 1.79; 1.80; 1.296; 1.81; 1.82; 1.83;1.84; 1.85; 1.86; 1.87; 1.88; 1.89; 1.90; 1.91 ; 1.92; 1.93; 1.94; 1.95; 1.96; 1.97; 1.98; 1.99; 1.100; 1.297; 1.101 ; 1.102; 1.103; 1.104; 1.105; 1.107; 1.298; 1.108; 1.109; 1.110; 1.112; 1.113; 1.118; 1.119; 1.120; 1.121 ; 1.122; 1.123; 3.2; 1.124; 1.125; 1.126; 1.127; 1.128; 1.129; 1.130; 1.131; 1.132; 2.1 ; 1.133; 2.2; 2.3; 1.134; 2.4; 1.299; 1.135; 3.3; 1.136; 3.6; 3.7; 3.5; 3.4; 1.137; 1.138; 1.139; 1.140; 1.141; 1.142; 1.143; 1.144; 1.145; 1.146; 4.1 ; 1.149; 1.150; 1.300; 1.162; 1.166; 1.167; 1.168; 1.301; 1.302; 1.303; 1.173; 1.177; 1.178; 1.179; 1.183; 1.184; 1.185; 1.188; 2.5; 2.6; 1.189; 2.7; 2.8; 1.190; 1.191; 1.192; 1.193; 1.194; 1.196; 2.9; 2.10; 2.11; 2.12; 2.13; 2.14; 2.138; 2.16; 1.197; 1.202; 1.203; 1.204; 1.207; 1.208; 1.209; 1.210; 1.211; 1.213; 1.214; 1.215; 1.218; 1.219; 1.220; 1.221; 1.223; 1.224; 1.225; 1.226; 1.227; 1.228; 1.229; 1.230; 1.231; 1.232; 1.233; 1.234; 1.235; 1.236; 1.237; 1.238;1.239; 1.240; 1.241 ; 1.242; 1.243; 1.247; 1.248; 1.249; 1.250; 1.252; 1.253; 1.254; 1.256; 1.257; 1.259; 1.320;1.260; 1.261 ; 1.262; 1.263; 1.264; 1.266; 1.267; 1.268; 1.269; 1.270; 1.271; 1.272; 1.273; 1.275; 1.276; 1.277;1.278; 2.26; 2.28; 2.30; 2.32; 2.34; 2.36; 1.279; 1.280; 1.324; 2.38; 2.39; 2.41; 2.42; 1.281; 1.282; 1.283; 1.284;1.285; 1.286; 1.289; 1.291 ; 1.292; 1.293; 1.294; 1.325; 1.326; 1.327; 1.328; 1.329; 1.330; 1.331 ; 1.332; 1.333;1.334; 2.43; 2.44; 2.45; 2.46; 2.47; 2.48; 2.49; 2.50; 2.51; 2.52; 1.335; 1.336; 1.337; 1.338; 1.339; 1.342; 1.344;1.345; 1.346; 2.53; 2.54; 2.55; 2.56; 2.57; 2.58; 2.59; 2.60; 2.61 ; 2.62; 2.63; 2.64; 1.347; 2.65; 2.66; 2.67; 2.69; 2.70; 1.348; 1.349; 1.350; 1.351; 1.352; 1.353; 1.354; 1.355; 1.356; 1.357; 1.358; 1.359; 1.360; 4.2; 4.3; 4.4; 4.6; 1.363; 1.364; 1.365; 1.366; 1.367; 1.368; 1.369; 1.370; 1.371; 1.372; 1.373; 4.7; 4.8; 4.9; 4.10; 2.71; 2.72; 1.374; 1.375; 1.376; 1.377; 1.378; 1.379; 1.380; 1.381; 1.384; 1.385; 1.386; 1.387; 1.388; 1.389; 1.390; 1.391 ; 1.392;1.393; 1.394; 1.395; 1.396; 1.397; 1.398; 1.399; 1.400; 1.401 ; 1.402; 1.403; 1.404; 1.405; 1.406; 1.407; 1.408;1.409; 1.410; 1.411 ; 1.412; 1.413; 1.414; 1.415; 1.416; 1.417; 1.418; 1.425; 1.428; 1.429; 1.430; 1.431 ; 1.432;1.433; 1.434; 1.435; 1.437; 1.438; 1.439; 1.440; 1.441 ; 1.442; 1.443; 1.444; 1.445; 1.446; 1.447; 1.448; 1.449;1.450; 1.451 ; 1.452; 1.453; 1.454; 1.455; 1.456; 1.457; 1.458; 1.459; 1.460; 1.461; 1.462; 1.463; 1.464; 1.465;1.466; 1.469; 2.73; 2.75; 2.76; 2.78; 2.77; 2.79; 1.472; 1.473; 1.475; 1.476; 1.477; 2.80; 2.81; 2.82; 1.478; 1.480; 1.482; 1.483; 1.484; 1.485; 1.487; 1.488; 1.489; 1.493; 1.494; 1.495; 1.496; 1.497; 1.501; 1.504; 2.83; 2.84; 2.85; 2.86; 2.87; 2.88; 1 .505; 2.89; 2.139; 2.90; 2.92; 2.140; 2.93; 1 .507; 1.508; 1.509; 1 .512; 1 .514; 1 .517; 1 .518; 1 .522; 1.527; 1.529; 2.94; 2.95; 1.532; 1.533; 1.534; 1.535; 1.536; 1.537; 1.538; 1.539; 1.540; 1.541 ; 1.542; 1.543; 1.544; 1.545; 1.547; 1.548; 2.96; 2.97; 1.551; 2.98; 2.99; 2.100; 2.101; 2.102; 1.554; 2.103; 2.104; 1.556; 1.558; 2.105;2.106; 1.559; 1.560; 2.107; 2.141 ; 2.108; 1.579; 2.109; 1.581 ; 1.582; 1.590; 1.591 ; 1.592; 1.593; 1.594; 1.595;1.596; 2.1 10; 1.599; 1.600; 1.601 ; 2.1 11 ; 1.605; 1.608; 1.609; 1.610; 2.1 12; 2.1 14; 2.1 13; 2.1 15; 2.1 16; 2.1 17;2.1 18; 1.615; 2.120; 2.121 ; 2.122; 2.123; 1.617; 1.618; 1.619; 1.620; 1.629; 2.125; 2.126; 2.127; 1.631 ; 1.633;1.634; 1.635; 1.638; 1.639; 1.641 ; 1.642; 1.643; 1.644; 1.645; 1.646; 1.647; 2.128; 2.129; 2.130; 2.131 ; 2.132;2.133; 2.134; 2.135; 2.136; 2.137; 1.650; 2.142; 2.143; 2.144; 2.145; 1.653; 2.146; 2.147; 1.654; 1.655; 2.148;1.657; 1.658; 1.659; 1.660; 1.661 ; 1.662; 2.149; 2.150; 2.151 ; 2.152; 2.153; 1.663; 2.154; 2.155; 1.664; 1.665;1.666; 1.667; 1.668; 1.669; 1.671 ; 1.672; 1.673; 2.160; 2.161 ; 1.674; 1.675; 1.676; 1.677; 2.162; 2.163; 2.164;1.679; 1.680; 1.681 ; 1.682; 1.683; 1.684; 1.685; 1.689; 1.690; 1.691 ; 1.692; 1.693; 2.167; 1.700; 1.701 ; 1.703;2.168; 1.707; 2.169; 2.170; 2.171 ; 2.173; 2.175; 1.710; 1.71 1 ; and 1.712.24) Another embodiment relates to a compound according to embodiment 1 ) which is : (6R, 12aS, 15aR)-11 -(4, 4-D if luorocyclohexyl)-3, 6-d i methyl-6,7, 8, 9, 10, 1 1 , 13, 14, 15, 15a- decahydrocyclopenta[e]pyrido[2,3-b]

[0001] oxa[4]thi a[8]azacyclotrideci n- 12(12aH)-one 16, 16-dioxide;(6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-17-imino-3,6-dimethyl-6,7,8,9, 10,11 , 12a, 13, 14,15- decahydro-12H, 17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(6R, 12aS, 17S)-1 1 -((3R,6s)-1 , 1 -Difl uorospi ro[2 ,5]octan-6-yl)-3, 6-di methyl- 17-(methy I i mi no)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-py rido[2,3-b]py rrolo[ 1 ,2- e]

[0001] oxa[4]thi a[5, 8]d i azacyclotrideci n-12-one 17-oxide;(6R, 1 1 aS)-10-((3R,6s)-1 , 1 -D if I uorospiro[2.5]octan-6-y l)-3, 6-d i methy I-7, 8, 9, 10, 1 1 a, 12, 13, 14-octahydropyrido[2,3- b]pyrrolo[ 1 , 2-e]

[0001] oxa[4]thi a[5, 8]di azacyclododeci n- 11 (6H)-one 16, 16-dioxide;(6R, 12aS)-11 -(4,4-Dif I uorocyclohexy l)-3, 6-di methyl-6, 7, 8, 9, 10, 1 1 , 12a, 13, 14, 15-decahydro-12H-pyrido[2,3- b]pyrrolo[ 1 , 2-e]

[0001] oxa[4]thi a[5, 8]di azacyclotrideci n- 12-one 17, 17-dioxide;(6R, 12aS)-11 -((3 R,5s)-1 , 1 -D if I uorospiro[2.3]hexan-5-y l)-3, 6-d i methy I-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H- pyrido[2,3-b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17, 17-dioxide;(1 R,4s)-4-((6R, 12aS)-3,6-Dimethyl-17, 17-dioxido-12-oxo-7,8,9,10, 12a,13, 14, 15-octahydro-6H-pyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11 (12H)-yl)-1-methylcyclohexane-1 -carbonitrile; or (1 R,4s)-4-((6R, 12aS)-4-FI uoro-3, 6-d imethy I- 17, 17-d ioxido- 12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro-6H- benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11 (12H)-yl)-1 -methylcyclohexane- 1 -carbonitrile.25) In addition to the compounds listed in embodiment 23), a further embodiment relates to a compound according to embodiment 1) which is:(6R, 12aS, 17S)-1 1 -((3R,6s)-1 , 1 -Difl uorospi ro[2 ,5]octan-6-yl)-3, 6-di methyl- 17-(methylimino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin- 12-one 17-oxide;(6R, 12aS, 17S)-11 -((3R,6s)-1 , 1 -D if luorospiro[2.5]octan-6-yl)-3, 6-di methy I- 17-((methyl-d3)imino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin- 12-one 17-oxide;(12S,51S,53S,2R)-8-((3R,6s)-1 , 1 -Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cyclohexanacyclononaphan-9-one 2-oxide;(12S,51R,53R,2S)-8-((3R,6s)-1 ,1 -Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cyclohexanacyclononaphan-9-one 2-oxide (1 R,4s)-1 -Methyl-4-((12S,51R,53R,2S)-36-methyl-2-(methylimino)-2-oxido-9-oxo-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cyclohexanacyclononaphane-8-yl)cyclohexane-1 -carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro-6H, 17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e]

[0001] oxa[4]thia[5,8]diazacyclotridecin-1 1 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro-6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e]

[0001] oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((8R, 12aS, 17S)-3,8-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e]

[0001] oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-1 -Methyl-4-((12S,51R,53R,2S)-34-methyl-2-(methylimino)-2-oxido-9-oxo-2λ6-4-oxa-2λ6-thia-8-aza-1 (1 ,2)- pyrrolidina-3(1 ,2)-benzena-5(1 ,3)-cydohexanacyclononaphane-8-yl)cyclohexane-1-carbonitrile;(1 R,4s)-1-Methyl-4-((6R,8R, 12aS, 17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-0X0-7,8,9, 10, 12a, 13, 14, 15- octahydro-6H, 17H-17λ4-benzo[b]pyrrolo[1 , 2-e]

[0001] oxa[4]th i a[5,8]d iazacyclotrideci n-11 (12H)-yl)cyclohexane-1 - carbonitrile;(6R, 12aS, 17S)-11 -((3R,6s)-1 , 1 -D if luorospiro[2.5]octan-6-yl)-3, 6-di methyl- 17-((methyl-d3) i mino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-py rido[2,3-b]py rrolo[ 1 ,2- e]

[0001] oxa[4]thi a[5, 8]d i azacyclotrideci n-12-one 17-oxide;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e]

[0001] oxa[4]thia[5,8]diazacyclotridecin-1 1 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e]

[0001] oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((8R, 12aS, 17S)-3,8-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e]

[0001] oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-1-Methyl-4-((6R,8R, 12aS, 17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-0X0-7,8,9, 10, 12a, 13, 14, 15- octahydro-6H, 17H-17X4-py rido[2,3-b]py rrolo[ 1 ,2-e]

[0001] oxa[4]th i a[5, 8]d i azacyclotrideci n- 1 1 (12H )-y IJcyclohexane- 1 - carbonitrile;(1 R,4s)-4-((6R, 12aS)-6-Ethyl-3-methy I- 17, 17-d ioxido- 12-oxo-6,7,9, 10, 12a, 13,14,15-octahydropyrido[2,3- e]pyrrolo[1 ,2-h][1,4]dioxa[7]thia[8,11 ]diazacyclotridecin-11 (12H)-yl)-1-methylcyclohexane-1-carbonitrile.For avoidance of doubt, the chemical names of said example compounds as listed in embodiments 22) to 25) are disclosed in the experimental part; and the corresponding structures of said example compounds are as shown in the experimental part, notably in the Table of Examples below, wherein, in case of doubt the depicted structure shall prevail.Thus, for example, the compound of example 2.14: (6R, 12aS,17S)-11-((3R,6s)-1, 1-difluorospiro[2.5]octan-6-yl)- 3, 6-di methyl- 17-(methy li m i no)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17 / ?-py rido[2, 3-b]py rrolo[ 1 ,2- e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide has the structure depicted in the Table of Examples, wherein said compound is in enriched absolute configuration as drawn:Likewise, the compound of example 1.40: (6R, 11aS)-10-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9, 10, 11 a, 12, 13, 14-octahyd ropy rido[2, 3-b]pyrrolo[ 1 , 2-e]

[0001] oxa[4]th ia[5, 8]di azacyclododeci n- 11 (6H)-one 16,16- dioxide has the structure depicted in the Table of Examples, wherein said compound is in enriched absolute configuration as drawn:Likewise, the compound of example 2.60: (1 R,4s)-1-Methyl-4-((12S,51R,53R,2S)-36-methyl-2-(methylimino)-2- oxido-9-oxo-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)-pyridina-1 (1,2)-pyrrolidina-5(1,3)-cyclohexanacyclononaphane-8- yl)cyclohexane-1 -carbonitrile, has the structure depicted in the Table of Examples, wherein said compound is in enriched absolute configuration as drawn:The compounds of formula (I) according to embodiments 1) to 25) 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 notably parenteral administration (including especially intravenous administration, as well as intramuscular or subcutaneous administration, or topical application or inhalation).The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.The present invention also relates to a method for the prevention / 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 25).For avoidance of any doubt, if compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.The compounds of Formula (I) according to any one of embodiments 1) to 25) are useful for the prevention / 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 roleare 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).Thus, the compounds of Formula (I) according to embodiments 1) to 25) 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 / prophylaxis or treatment of:> hypersomnia, particularly prevention / 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);> (secondary) narcolepsy associated with tumors, especially symptoms of narcolepsy associated with tumors that involve the hypothalamus area;> (secondary) narcolepsy associated with head trauma, especially symptoms of narcolepsy associated with head trauma affecting the hypothalamic area;> idiopathic hypersomnia;> Kleine-Levin syndrome;> excessive daytime sleepiness (EDS), particularly: o improving symptoms of EDS in subjects having a circadian rhythm sleep-wake disorder, particularly improving symptoms of EDS in subjects having: delayed sleep-wake phase disorder, shift work disorder, or jet lag disorder; o improving symptoms of EDS due to or associated with a medical disorder, wherein 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 objective sleep disturbances (notably sleep apnea);■ improving symptoms of EDS associated with obesity and / or diabetes;■ 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;■ improving symptoms reminiscent of narcolepsy in subjects having an auto-immune disorder (especially neuromyelitis optica, multiple sclerosis, Guillain-Barre syndrome, or anti-Ma2 encephalitis);■ improving symptoms of EDS / treatment of hypersomnia associated with a psychiatric disorder, such as depression; or■ improving symptoms of EDS / treatment of hypersomnia associated with insufficient sleep syndrome; or o improving symptoms of EDS / treatment of hypersomnia due to a medication or substance; or> fatigue (especially including chronic fatigue), particularly:■ (chronic) fatigue accompanied by poor concentration and memory;■ (chronic) fatigue associated with infections (viral or bacterial), (chronic) inflammatory diseases, cancer or chemotherapy, or neurological diseases or neurodegeneration;■ (chronic) fatigue associated with autoimmune diseases including Sjogren's syndrome and multiple sclerosis; or■ fatigue associated with myalgic encephalomyelitis / chronic fatigue syndrome.The term “narcolepsy type 1” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep disruption and cataplexy (loss of muscle tone in full consciousness often triggered by positive emotions).The term “narcolepsy type 2” describes a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), sleep attacks, hallucinations, sleep paralysis, sleep disruption and without 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 physical and / or mental exhaustion").Further disease and disorders in which agonism of OX2R plays a role include:> eating disorders;> obesity, particularly obesity in narcoleptic subjects;> attention deficit disorders, including attention deficit hyperactivity disorder (ADHD);> neuropsychiatric disorders, notably mood disorders, in particular mood disorders associated with reduced hedonic drive, particularly depression (such as major depressive disorder (MDD)), schizophrenia, addiction, or PTSD;> pain, particularly inflammatory pain, or chronic neuropathic pain;> inflammation, particularly inflammation following cardiac arrest, intracerebral hemorrhage, or septic shock; and> cognitive impairments, particularly age-related deficits in learning and memory or cognitive impairments due to sleep loss.I Additionally, agonism of OX2R plays a role in:> disorders of consciousness, notably coma, vegetative state and minimally conscious state induced by traumatic brain injury; and> recovery of arousal following unconsciousness associated with cardiac arrest or acute alcohol intoxication, or following anesthetic-induced unconsciousness.It is to be understood that in the context of using compounds of Formula (I) according to embodiments 1) to 25) for improving wakefulness in a subject (especially in a subject having hypersomnia or narcolepsy, or presenting excessive daytime sleepiness (EDS)), other symptoms or disease characteristics of that subject may be concurrently improved. For example, in the context of using compounds of Formula (I) according to embodiments 1) to 24) for improving symptoms of EDS due to or associated with diabetes, other symptoms or disease characteristics of that subject may be concurrently improved, e.g., in addition to improving wakefulness in a diabetic subject, diabetic parameters may be improved.In the context of the present invention, 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 25) are in particular useful as therapeutic agents for the prevention / 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. Such therapeutic agents include modafinil, pitolisant, sodium oxybate, solriamfetol, armodafinil, dextroamphetamine, methylphenidate, clarithromycin, venlafaxine, clomipramine and lithium (see for example Maski K. et al. J Clin Sleep Med. 2021 , 17(9), 1881-1893; Bassetti 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 25);> 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 25);> and instructions how to use said pharmaceutical composition for improving wakefulness in a subject presenting excessive daytime sleepiness (EDS).Besides, 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) and Formula (III).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 theirbioavailability 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. in rats after oral dosing; or relating to their functional behavior in different disease related animal models (for example: the general stimulant effect of the compound using Electroencephalography (EEG) and Electromyography (EMG) signal measurements [Yukitake H et al.; TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice; Pharmacol Biochem Behav. 2019, 187:172794], the effect of the compound on narcolepsy-cataplexy symptoms [Irukayama-Tomobe Y et al.; Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models; Proc Natl Acad Sci U S A. 2017, 114(22):5731 -5736]); or for their properties with regard to drug safety and / or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.Preparation of compounds of Formula (I)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 R1, R2, RA1, X1, X2, X3, X4, L, X5, Ring A, Ring B, Ring E, Ring F, are as defined for Formula (I). Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In some instances the generic groups R1, R2, RA1, X1, X2, X3, X4, X5, L, Ring A, Ring B, Ring E, Ring F might be incompatible with the assembly illustrated in the schemes below and so will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse.General preparation routes;The general route described here below allows to prepare compounds of Formula I. The synthesis of some specific examples might not be included and differ from the general route described here. In this case, the synthesis of these specific compounds is described in the experimental procedure here below.Preparation of Sulfonamide Compounds (Examples 1.x)Compound A.13, belonging to Formula (I) wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by an 0 atom (i.e., L represents O-L01), can be prepared as described in Scheme A.1. Aldehyde A.1 can be reacted with a primary amine (or the corresponding salt, like HCI or TFA salts) in presence of a primary amine A.2 using a solvent such as MeOH or THF, or DCM and in presence of a reducing agent such as NaBFU, NaBHsCN or NaBH(OAc)3 to give secondary amine A.3. Aldehyde A.1, wherein PG is an appropriate hydroxy protecting group such as TBDPS-, TBDMS-, or Bn, can be prepared from commercially available scaffolds following proceduresknown in the literature and familiar to the person skilled in the art or as reported in the experimental procedure here below. Secondary amine A.3 can be protected with an appropriate protecting group (PG1) such as Boc, Cbz, Bn or other using standard protection methods known in the literature and familiar to the person skilled in the art to give intermediate A.4. The protected primary alcohol (PG) of A.4 can be deprotected using standard procedures known in the literature and familiar to the person skilled in the art to yield A.5. Amine A.7 is condensed with a sulfonyl chloride A.6 in a solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA to give A.8. Intermediate A.6 can be commercially available, prepared following procedures known in the literature, or prepared as described in the experimental part here below. Intermediate A.8 can be demethylated using BBr3in a solvent such as DCM to yield A.9. Intermediate A.9 can be reacted with primary alcohol A.5 in a Mitsunobu reaction using a reagent such as DEAD or DIAD and PPhs in a solvent such as THF to yield A.10. The amine protecting group (PG1) can be removed with standard procedures known in the literature and familiar to the person skilled in the art to yield A.11. The ester functional group of A.11 can be deprotected under acidic or basic conditions to yield A.12. When Alk=Me, the hydrolysis can occur in presence of a base such as LiOH in a solvent such as THF / H2O, while when Alk= t-Bu the hydrolysis can occur under acidic conditions using TFA in a solvent such as DCM or HCI in 1 ,4- dioxane. Finally, intermediate A.12 can be cyclized via an intermolecular amide coupling 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 to yield macrocycle A.13.Scheme A.1. Synthesis of sulfonamide macrocycles A.13Alternatively, macrocycles A.13 can be prepared as described in Scheme A.2. Hydroxy scaffold A.14, wherein PG is an appropriate protecting group such as Bn, TBDMS, TBDPS, or similar, can be reacted with A.9 in a Mitsunobu reaction using a coupling reagent such as DEAD or DIAD and PPha in a solvent such as THF to yield A.15. Mono- protected diols A.14 can be prepared following known procedure described in the literature or in analogy to it, or as reported in the experimental part here below. Protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative A.16. Oxidation of the primaryalcohol of derivative A.16 using oxalyl chloride and TEA in DMSO, or sulfur trioxide pyridine complex and TEA in DMSO can yield aldehyde A.17. Aldehyde A.17 can be reacted with a primary amine (or the corresponding salt, like HCI or TFA salts) (A.2) using a solvent such as MeOH or THF, or DCM and in presence of a reducing agent such as NaBH4, NaBHsCN or NaBH(AcOAc)3 to give secondary amine A.11. Hydrolysis of the ester functional group of A.11 into the corresponding carboxylic acid (A.12) can be performed in a similar way as described for above. Intermediate A.12 can be cyclized via an intermolecular amide coupling 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 to yield macrocycle A.13. Intermediate A.16 can alternatively be prepared by reacting intermediate A.9 with terminal alkene alcohol A.18 via a Mitsunobu reaction using a reagent such as DEAD or DIAD and PPhs in a solvent such as THF to give A.19. Terminal alkene A.19 can undergo a hydroboration / oxidation using BH3.THF complex in a solvent such as THF, followed by oxidation using an oxidizing agent as H2O2 and an aqueous soln, of NaOH in a solvent such as THF to yield A.16. Intermediate A.16 can be oxidized into the corresponding aldehyde (A.17) for example using a reagent such as SOs.pyridine in a solvent such as DMSO and a base as TEA , oxalyl chloride and TEA in DMSO, or again Dess-Martin periodinane in a solvent such as DCM. Aldehyde A.17 can be reacted with primary amine A.2 in presence of a reducing agent such as NaBH4, NaBHsCN or NaBH(OAc)3 in a solvent such as MeOH or THF, or DCM to give secondary amine A.11. Intermediate A.11 can be converted to A.13 as described here above in Scheme A.1.Scheme A.2. Alternative synthesis of sufonamide macrocycles A.13An alternative route for the preparation of key intermediate A.15 is described in Scheme A.3. Reaction of scaffoldA.20 via a Mitsunobu reaction using a reagent such as DEAD or DIAD and PPhs in a solvent such as THF yieldsA.22. Alternatively, A.22 can also be prepared from A.21 via a SNAr reaction with A.14 using a base such as NaH in a solvent such as THF. Intermediate A.22 can be reacted in presence of a catalyst such as Pd2(dba)3 and a ligand such as XantPhos or a precatalyst such as Xanthphos-Pd-G3 or Xanthphos-Pd-G2, mercaptan, a base such as DIPEA in a solvent like 1 ,4-dioxane and under heating. As an alternative, intermediate A.23 can be prepared by lithium-halogen exchange treating A.22 with a reagent such as n-BuLi and reacting the resulting organolithium reagent with benzyl disulfide in a solvent such as THF, or by a SNArreaction in presence of mercaptan and a base such as NaH in a solvent such as DMF at it Intermediate A.23 can be converted into its analogue sulfonyl chloride A.24 by treatment with 1 ,3-dichloro-5,5-dimethylhydantoin in a solvent mixture as 1,4-dioxane. Reaction between A.24 and amine A.7 in a solvent such as DOM, DMF, or MeCN and in presence of a base such as TEA or DIPEA yields intermediate A.15. Finally, intermediate A.15 can also be prepared treating A.20 with 2-ethylhexyl 3- mercaptopropionate in presence of a catalyst as Pd2(dba)3 and a ligand as Xantphos and a base such as DIPEA in a solvent as toluene and at a temperature of 90°C to give A.25. In turn, intermediate A.25 can be oxidized using an oxidant such as m-CPBA in a solvent such as DOM at rt into sulfone A.26. Reaction between A.26 and primary alcohol A.14 in presence of a reagent such as DEAD or DIAD and PPha in a solvent such as THF yields A.27. Intermediate A.27 can be treated with NaOMe soln, in MeOH in a solvent such as THF, followed by NOS to give the corresponding sulfonyl chloride which can be reacted with A.7 and a base such as TEA in THF to yield intermediate A.15. Intermediate A.15 can be converted to macrocycles A.13 following the same procedure here above in Scheme A.2.Scheme A.3. Alternative synthesis of sulfonamide intermediate A.15In another aspect, macrocycles A.32, belonging to Formula (I) wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by an 0 atom (i.e., L represents O-L01) can also be prepared as described in Scheme A.4 starting from intermediate A.19 by ester hydrolysis. When Alk=Me, the hydrolysis can occur in presence of a base such as LiOH in a solvent such as THF / H2O, while when Alk= t-Bu the hydrolysis can occur under acidic conditions using TFA in a solvent such as DCM or HCI in 1 ,4-dioxane to give A.28. Reaction between carboxylic A.28 and secondary amine A.29 in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA or N-methylmorpholine in a solvent such as THF, DMF, DCM or MeCN yields A.30. Amines A.29 are either known in the literature or can be prepared using known methodologies in the literature and familiar to the person skilled in the art. Intermediate A.30 can be treated with a catalyst such as 2ndgeneration Grubbs Catalyst or similar in a solvent such as DCM at reflux to give macrocycle A.31. Finally, the endocyclic double bond can be reduced by treating A.31 with a catalyst such as Pd / C and H2 in a solvent such as MeOH or EtOH to give macrocycles A.32.Scheme A.4. Synthesis of sulfonamide macrocycles A.32Compound A.40, belonging to Formula (I) wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by a C atom and L represents an unsubstituted carbon chain (such that q = 1 to 5), can be prepared as described in Scheme A.5. Intermediate A.34 can be prepared by treating sulfonyl chloride A.33 with amine A.7 in a solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA. Intermediate A.34 can be reacted with 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2-dioxaborolane and a catalyst such as (dppfJPdCk CH2CI2, a base such as K2CO3, in a solvent such as dioxane / H2O to yield A.35. Hydrolysis of the ester can occur in presence of a base such as LiOH in a solvent such as THF / H2O when Alk=Me, or under acidic conditions using TFA in a solvent such as DCM or HCI in 1,4-dioxane when Alk= t-Bu to give A.36. Intermediate A.36 can be condensed with amine A.37 using a coupling reagent such as BTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA or N- methylmorpholine in a solvent such as THF, DMF, DCM or MeCN to yield A.38. Amine A.37 can be prepared using known methodologies in the literature and familiar to the person skilled in the art. Reaction of A.38 with a catalyst such as such as 2ndgeneration Grubbs catalyst or similar in a solvent such as DCM can give macrocycle A.39. Theendocydic double bond of A.39 can be reduced in presence of a catalyst such as Pd / C under a H2 atm in a solvent such as MeOH or EtOH to give macrocycles A.40.Scheme A.5. Synthesis of sulfonamide macrocycles A.40. Macrocycles A.46, belonging to Formula I wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by a C atom (i.e., L represents C-LC1), can be prepared as described in Scheme A.6. Intermediate A.34 can be treated with a terminal alkyne (A.41) in presence of a catalyst as for example Pd(PPh3)4, a co-catalyst such as Cui and a base such as Eta N or DIPEA in a solvent such as DMF to yield A.42. Terminal alkynes A.41 are either commercially available, known in the literature, or can be prepared from simple scaffolds using methodologies known in the literature and familiar to the person skilled in the art. Intermediate A.42 can be reduced in presence of a catalyst such as Pd / C under a H2 atm in a pressurized autoclave or using a flow reactor to yield A.43. Deprotection of A.43 using methodologies known in the literature and familiar to the person skilled in the art can yield A.44. Hydrolysis of A.44 to A.45 can be performed as described here above for the preparation of A.36. Finally, intermediate A.45 can be converted into macrocycle A.46 in presence of coupling reagent such as BTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA or N-methylmorpholine in a solvent such as THF, DMF, DCM or MeCN.Scheme A.6. Synthesis of macrocycle compounds A.46.Compound A.55, belonging to Formula (I) wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by a N atom (i.e., L represents N-LN1), can be prepared as described in Scheme A.7. Intermediate A.52 can be prepared by treating sulfonyl chloride A.51 with amine A.7 in a solvent such as DCM, DMF, MeCN and in presence of a base such as TEA or DIPEA. Intermediate A.52 can be reacted with amine A.50 in presence of a base such as DIPEA or TEA in a solvent such as DMSO to yield A.53. Amines A.50 can be prepared reacting amine A.47 (commercially available, known in the literature, or prepared from known methododologies familiar to the person skilled in the art) and primary amine A.2 (or the corresponding salt, like HCI or TFA salts) using a solvent such as MeOH or THF, or DCM and in presence of a reducing agent such as NaBFU, NaBH3CN or NaBH(AcOAc)3 to give secondary amine A.48, followed by orthogonal PG deprotection using methodologies known to the person skilled in the art to give A.50. Intermediate A.53 can be deprotected (PG1) using methodologies known in the literature and the ester can be hydrolysed using a base such as LiOH in a solvent such as THF / H2O when Alk=Me, or under acidic conditions using TFA in a solvent such as DCM or HCI in 1,4-dioxane when Alk= t-Bu, to give intermediate A.54. Intramolecular cyclization of A.54 can be conducted using a coupling reagent such as BTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA or N-methylmorpholine in a solvent such as THF, DMF, DCM or MeCN to yield A.55. Alternatively, A.52 can be reacted with amine A.56 in presence of a base such as DIPEA or TEA in a solvent such as DMSO to yield A.57. Amine A.56 can be commercially available or prepared following procedures known in the literature. Intermediate A.57 can be deprotected using known methodologies familiar to the person skilled in the art. Treatment of A.58 using oxalyl chloride and TEA in DMSO, or sulfur trioxide pyridine complex and TEA in DMSO can yield aldehyde A.59. Aldehyde A.59 can be reacted with a primary amine (or the corresponding salt, like HCI or TFA salts) (A.2) using a solvent such as MeOH or THF, or DCM and in presence of a reducing agent such as NaBH4, NaBH3CN or Na(AcOAc)3to give A.60. Hydrolysis of the ester functional group into the corresponding carboxylic acid can be performed in a similar way as described here above in Scheme A.1 . The resulting carboxylic acid can be coupled intramolecularly by amide coupling 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 DI PEA, TEA or N-methylmorpholine to give A.55.Scheme A7. Synthesis of macrocycle compounds A.55.Compound A.66, belonging to Formula (I) wherein X3= SO2, X4=NRN1, X5=C, and wherein L is linked to Ring A by a N atom (i.e. , L represents N-LN1) and q=1 to 4, can be prepared as described in Scheme A.8. Intermediate A.52 can be reacted with amine A.61 in presence of a base such as DIPEA or TEA in a solvent such as DMSO to yield A.62. Hydrolysis of the ester as described here above yields A.63. Reaction between carboxylic A.63 and secondary amine A.37 (or the corresponding salt, like HCI or TFA salts) in presence of a coupling reagent such as TBTU, HBTU, HATU, EDC (or similar) and a base such as DIPEA, TEA or N-methylmorpholine in a solvent such as THF, DMF, DCM or MeCN can yield A.64. Intermediate A.64 can be treated with a catalyst such as 2ndgeneration Grubbs catalyst or similar in a solvent such as DCM at reflux to give macrocycle A.65. Double bond reduction can be performed treating A.65 with a catalyst such as Pd / C and H2 in a solvent such as MeOH or EtOH to give macrocycles A.66.Scheme A.8. Synthesis of sulfonamide macrocycles A.66Preparation of SIA Compounds (Examples 2.x)Compounds B.8 and B.9, belonging to Formula (I) wherein X3= S(O)(NR3), R3=H / Alkyl, X4=NRN1, X5=C, and wherein L is linked to Ring A by an 0 atom (i.e., L represents O-L01), can be prepared as described in Scheme B.1. Intermediate B.1 can be prepared by lithium-halogen exchange treating A.22 with a reagent such as n-BuLi and reacting the resulting organolithium reagent with tert-butyl (oxo-λ4-sulfaneylidene)carbamate in a solvent such as THF. Sulfinamide B.1 can be treated with tert-butyl hypochlorite to give the corresponding sulfonimidoyl chloride, which can be reacted with amine A.7 and a base such as DIPEA in DCM to yield SIA B.2. Hydroxy protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative B.3. Oxidation of the primary alcohol using oxalyl chloride, TEA and DMSO in DCM can yield aldehyde B.4. Aldehyde B.4 can be reacted with a primary amine (or the corresponding salt, like HCI salts) (A.2) in presence of a base, such as DIPEA using a solvent such as MeOH and in presence of a reducing agent such as NaBH4 to give secondary amine B.5. Hydrolysis of the ester functional group of B.5 into the corresponding carboxylic acid can be performed in a similar way as described for the hydrolysis of A.11 into A.12 to give B.6. Intermediate B.6 can be cyclized via an intermolecular amide coupling in a solvent such as DMF in presence of a coupling reagent such as HATU and a base such as DIPEA to yield macrocycle B.7. Sulfonimidamide Boc protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative B.8. Alkylation of intermediate B.8 can be performed in the presence of alkyl iodide and NaH as a base in DMF to afford B.9. Generated diastereomers can be separated either by prep HPLC, flash chromatography or chiral SFC chromatography.Scheme B.1. Synthesis of macrocycle compounds B.8 and B.9.Alternatively, derivatives B.8 and B.9 can be prepared as described in Scheme B.2. Thioether A.25 can react with alcohol A.5 via a Mitsunobu reaction using a reagent such as DEAD and PPha in a solvent such as THF to yield B.10. Reacting intermediate B.10 with a base such as NaOMe in MeOH provides the corresponding thiol B.11.Thiol B.11 can be oxidized into its corresponding sulfinate ester B.12 by reaction with NBS and MeOH in a solvent such as DCM. Sulfinate ester B.12 can be converted into sulfinamide with general structure B.13 by reaction with LiHMDS in a solvent like THF and hydrolysis with sat. aq. NH4CI. The resulting sulfinamide can be protected with an appropriate protecting group (PG2) such as Fmoc to yield B.14 using standard protection methods known in the literature and familiar to the person skilled in the art. Compound B.14 can be condensed with amine A.7 in presence of a chlorinating agent such as tert-butyl hypochlorite in a solvent such as DCM to give intermediate B.15. Hydroxy and amine protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative B.16. Intermediate B.16 can be cyclized via an intermolecular amide coupling in a solvent such as DMF in presence of a coupling reagent such as HATU and a base such as DIPEA to yield macrocycle B.17. Deprotection of PG2using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative B.8. Alkylation of intermediate B.8 can be performed in the presence of alkyl iodide and NaH as a base in DMF to afford B.9. Generated diastereomers can be separated either by prep HPLC, flash chromatography or chiral SFC chromatography.Scheme B.2. Alternative synthesis of macrocycle compounds B.8 and B.9.Preparation of Sulfone Compounds (Examples 3.x)Compounds C.13, belonging to Formula (I) wherein X3= SO2, X4=CHRC1, X5=C, and wherein L is linked to Ring A by an 0 atom (i.e., L represents O-L01), can be prepared as described in Scheme C.1. Michael addition between arylthiol C.1 and commercially available a,p-unsaturated ester C.2 in a solvent such as piperidine yields thioether C.3. Intermediate C.3 can be oxidized in presence of an oxidant such as m-CPBA and a base such as NaHCO3, in a solvent such as DCM to provide sulfone C.4. Intermediate C.5 can be prepared by treating C.4 with 4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane in presence of a catalyst such as PdCl2(MeCN)2, a ligand such as SPhos and a base such as TEA in a solvent such as dioxane. Intermediate C.5 can be oxidized in presence of an oxidant such as H2O2 and a base such as NaOH in a solvent such as THF to provide intermediate C.6. Alternatively, C.6 can be synthesized reacting scaffold A.21 with thiol C.7 in presence of a catalyst such as XantPhos Pd G2 and a base such as DIPEA in dioxane to give the corresponding thioether C.8. In turn, intermediate C.8 can be oxidized using an oxidant such as m-CPBA and a base such as NaHCO3in a solvent such as DCM to provide sulfone C.9. Intermediate C.9 can be treated with aqueous acid such as HCI (6M) in a solvent such as MeOH at reflux to give derivative C.6. Scaffold C.6 can be reacted with alcohol A.5 via a Mitsunobu reaction using a reagent such as DEAD and PPh3in a solvent such as THF to yield derivative C.10. Hydrolysis of the ester functional group of C.10 into the corresponding carboxylic acid can be performed in a similar way as described for the hydrolysis of A.11 into A.12 to give C.11. Amine protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative C.12. Intermediate C.12 can be cyclized via an intermolecular amide coupling in a solvent such as DMF in presence of a coupling reagent such as HATU and a base such as DIPEA to yield macrocycle C.13. Generated diastereomers can be separated either by prep HPLC, flash chromatography or chiral SFC chromatography.Scheme C.1 . Synthesis of macrocycle compounds C.13.An alternative synthesis of macrocycles C.13 is depicted in Scheme C.2. Building block A.20 can be reacted with thiol C.7 in presence of a catalyst such as XantPhos Pd G2 and a base such as DIPEA in dioxane to give the corresponding thioether C.14. Thioether C.14 can be treated with an acid such as sulfuric acid in MeOH at reflux to give derivative C.15. Ester C.15 can be reacted with alcohol A.14 via a Mitsunobu reaction using a reagent such as DEAD and PPha in a solvent such as THF to yield derivative C.16. Hydroxy protecting group cleavage (PG1) using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative C.17. Oxidation of the primary alcohol using oxalyl chloride, TEA and DMSO in DCM can yield aldehyde C.18. Aldehyde C.18 can be reacted with a primary amine (or the corresponding salt, like HCI salts) in a solvent such as MeOH and in presence of a reducing agent such as NaBH(OAc)3 to give secondary amine C.19. Hydrolysis of the ester functional group of C.19 into the corresponding carboxylic acid can be performed in a similar way as described here above for the hydrolysis of A.11 into A.2 to give C.20. Intermediate C.20 can be cyclized via an intermolecular amide coupling in a solvent such as MeCN in presence of a coupling reagent such as HATU and a base such as DIPEA to yield macrocycle C.21. Intermediate C.21 can be oxidized with an oxidant such as m-CPBA in a solvent such as DCM to give sulfone macrocycle C.13.Scheme C.2. Alternative synthesis of macrocycle compounds C.13.On the other hand, intermediate A.25 can be reacted with alcohol A.14 via a Mitsunobu reaction using a reagent such as DEAD and PPha in a solvent such as THF to yield derivative C.22 as described in Scheme C.3. Intermediate C.22 can be treated with a base such as potassium tert-butoxide in a solvent such as THF to give molecule C.23.In turn, michael addition between intermediate C.23 and commercially available a,p-unsaturated ester C.2 in a solvent such as piperidine yields thioether C.16. Intermediate C.16 can be oxidized in presence of an oxidant such as m-CPBA and in a solvent such as DCM to provide sulfone C.24. Hydroxy protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative C.25. Oxidation of the primary alcohol using an oxidant such as NaOCI in presence of TEMPO, KBr and a base such as NaHCO3 and in a solvent such as DCM can yield aldehyde C.26. Aldehyde C.26 can be reacted with a primary amine (or the corresponding salt, like HOI salts) in a solvent such as MeOH and in presence of an acid such as AcOH and a reducing agent such as NaBH(CN)3 to give secondary amine C.27. Hydrolysis of the ester functional group of C.27 into the corresponding carboxylic acid can be performed in a similar way as described for the hydrolysis of A.11 into A.12 to give C.28. Intermediate C.28 can be cyclized via an intermolecular amide coupling in a solvent such as MeCN in presence of a coupling reagent such as HATU and a base such as DI PEA to yield macrocycle C.13.Scheme C.3. Alternative synthesis of macrocycle compounds C.13.Preparation of Sulfoximine Compounds (Examples 4.x)Compounds D.7, belonging to Formula (I) wherein X3= S(O)(NR3), R3= H, Alkyl, X4=CHRC1, and wherein L is linked to Ring A by an 0 atom (i.e., L represents O-L01), can be prepared as described in Scheme D.1. Scaffold A.20 can react with thiol C.16 in presence of a catalyst such as XantPhos Pd G2 and a base such as DIPEA in dioxane to give the corresponding thioether D.1. Esterification of the carboxylic acid functional group of D.1 into the corresponding ester can be performed in MeOH in presence of an acid such as sulfuric acid to give ester D.2. Intermediate D.2 can react with alcohol A.5 via a Mitsunobu reaction using a reagent such as DEAD and PPha in a solvent such as THF to yield D.3. Hydrolysis of the ester functional group of D.3 into the corresponding carboxylic acid can be performed in a similar way as described for the hydrolysis of A.11 into A.12 to give D.4. Amine protecting group cleavage using standard deprotection methods known in the literature and familiar to the person skilled in the art leads to derivative D.5. Intermediate D.5 can be cyclized via an intermolecular amide coupling in a solvent such as DMF in presence of a coupling reagent such as HATU and a base such as DI PEA to yield macrocycle D.6. Oxidation of thioether D.6 can be performed using an oxidant such as (diacetoxyiodo)benzene in presence of ammonium carbamate in a solvent such as MeOH to give sulfoximine D.7. Generated diastereomers can be separated either by prep HPLC, flash chromatography or chiral SFC chromatography.Scheme D.1 . Synthesis of macrocycle compounds D.7Experimental PartAbbrevations (as used herein and in the description above):Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)AcOH Acetic acidAik Alkyl (as explicitly defined) anh. Anhydrous aq. aqueous atm Atm tBME tert-ButylmethyletherBoc tert-ButoxycarbonylBOC2O di-fert-Butyl dicarbonate tBuOCI tert-Buthyl hypochloriteBSA Bovine serum albumineBu Butyl such as in tBu = tert-butyl = tertiary butyl ca. circaCAS Chemical Abstracts Services cone. ConcentratedDBU 1 ,8-Diazabicyclo(5.4.0)undec-7-eneDCDMH 1,3-Dichloro-5,5-dimethylhydantoinDCM DichloromethaneDEA DiethylamineDEAD Diethyl azodicarboxylateDIAD Bis(isopropyl) azodicarboxylateDI PEA DiisopropylethylamineDMAP 4-DimethylaminopyridineDME DimethoxyethaneDMEM Dulbecco’s modified eagle mediumDMF W,W-DimethylformamideDMSO Dimethyl sulfoxide dppf 1 , 1 '-Bis(diphenylphosphino)ferroceneEDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideELSD Evaporative Light-Scattering Detection eq Equivalent(s)ES Electron sprayEt EthylEt20 Diethyl etherEtOAc Ethyl acetateEtOH EthanolEx. ExampleFBS Fetal bovine serumFC Flash Chromatography on silica gelFCS Foatal calf serum h Hour(s)Hal Halogen (as explicitly defined)HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHBSS Hank’s balanced salt soln.HBTU 2-(1 H-benzotriazol-1-yl)-1 ,1,3,3-tetramethyluronium hexafluorophosphateHEK293 Human embryonic kidney 293 cellsHEPES 4-(2-Hydroxyethyl)-piperazine-1 -ethanesulfonic acidHept Heptane1H-NMR Nuclear magnetic resonance of the protonHPLC High performance liquid chromatographyHTRF Homogeneous Time Resolved FluorescenceIP1 Intracellular inositol-1 -phosphate iPr isopropyl / PrOAc Isopropyl acetate KHMDS Potassium hexamethyldisilazide LC-MS Liquid chromatography - Mass Spectroscopy □HMDS Lithium hexamethyldisilazide Lit. Literature M Exact mass (as used for LC-MS) M Molarity [mol L1] m-CPBA 3-Chloroperbenzoic acid Me Methyl MeCN Acetonitrile MeOH Methanol Mel Methyl iodide MHz Megahertz FC Medium performance liquid chromatography2-MeTHF 2-Methyltetrahydrofuran min Minute(s) MS Mass spectroscopy Ms Mesyl such as OMs N Normality NBS N-Bromosuccinimide NMP N-Methyl-2-pyrrolidone Org. OrganicPdCI2(MeCN)2Bis(acetonitrile)palladium(ll) chloridePd2(dba)3tris(dibenzylideneacetone)dipalladium(0)Pd(OAc)2Palladium diacetatePd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) PG Protecting group Ph PhenylPL-HCO3Polymer supported hydrogen carbonatePr propylPrep. PreparativePrOH PropanolPTFE PolytetrafluoroethylenePyCloP Chlorotripyrrolidinophosphonium hexafluorophosphatePyrSO3Sulfur trioxide pyridine complex rac Racemic or racemateRf Retention factor rt Room temperature sat. SaturatedSIA Sulfonimidamide compound(s)SFC Supercritical fluid chromatography soln. SolutionTBAF Tetra-n-butylammonium fluorideTBTU 2-(1 H-Benzotriazole-1 -yl)-1 , 1 ,3,3-tetramethylaminium tetrafluoroborate tBu fert-Butyl tBuOH tert-ButhanolTEA TriethylamineTEMPO 2,2,6,6-TetramethylpiperidinyloxyTf Triflate such as OTfTFA Trifluoroacetic acidTHF TetrahydrofuranTLC Thin layer chromatographyTMP 2,2,6,6-TetramethylpiperidineTMSI Trimethylsilyl iodide tR Retention timeTs Tosyl such as OTsUPLC Ultra performance liquid chromatographyXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxantheneXanthphos Pd G3 Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,T- biphenyl)]palladium(ll) (CAS: 1445085-97-1)I. ChemistryAll temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atm of N2. Compounds were purified by flash column chromatography on silica gel or by prep. HPLC. Compounds described in the invention are characterised by LC-MS data (retention time tRis given in min; molecular weight obtained from the mass spectrum is given in g / mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given. Racemates can be separated into their enantiomers by preparative HPLC or SFCLC-MS conditionsLC-MS 1LC-MS- conditions: Analytical UPLC on a Agilent Zorbax RRHD SB-Aq (2.1x50mm, 1.8 p.m); detection at 210 nM and MS; UPLC / MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; Gradient of H2O / 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):LC-MS 2LC-MS- conditions: Analytical UPLC on a Waters BEH C18 (2.1x50 mm, 2.5 p.m); detection at 210 nM and MS; UPLC / MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; gradient of H20 / 0.04% NH3 [c(NH3) = 13 mmol / l] (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):LC-MS 3LC-MS-conditions: Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector or Xevo TQD, DAD: Acquity UPLC PDA Detector. Column: Acquity UPLC CSH C18 1.7 p.m, 2.1 x 50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A1 : H2O + 0.05 % formic acid; B1 : MeCN + 0.045 % formic acid. 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 4LC-MS- conditions: Analytical UPLC on a Waters BEH C18 (2.1x50mm, 1.8 p.m); detection at 210 nM and MS; UPLC / MS analyses are performed on Acquity UPLC setup; the column temperature is 40°C; Gradient of H2O / 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 LC-MS methods used:Prep. 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 FLO / formic acid 0.02% (A) and MeCN (B) (acidic conditions) or FLO / ammonia 0.02% (A) and MeCN (B) (basic conditions).Preparative chiral SFC methods used:Prep, chiral SFC purifications were performed on a Sepiatec Prep SFC 360 system. Following parameters were used:Prep, chiral SFC 1: A ChiralCel OZ-H column (30 x 250mm, 5um) was used. The modifier was EtOH / MeCN 1 :1 , run for 4 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature pumphead 4 °C, temperature fraction module 20 °C, and temperature column department 40 °C.Prep, chiral SFC 2: A ChiralPak IB column (30 x 250 mm, 5 |im) was used. The modifier was MeCN / EtOH / DEA 50:50:0.1 (20%), run for 6.94 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature postheater 25 °C, temperature preheater 40 °C, and temperature column department 40 °C.Prep, chiral SFC 3'. A ChiralPak I J column (30 x 250 mm, 5 |im) was used. The modifier was MeOH (10%), run for 6.5 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.Prep, chiral SFC 4: A Regis (R,R)-Whelk-O1 column (30 x 250 mm, 5 |im) was used. The modifier was MeCN / 2- PrOH 50:50 (30%), 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.Prep, chiral SFC 5'. A Chiralpak ID column (30 x 250 mm, 5 |im) was used. The modifier was 2-PrOH (45%), run for 5 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature postheater 35 °C, temperature preheater 40 °C, and temperature column department 40 °C.Prep, chiral SFC 6: A ChiralPak OX-H column (30 x 250 mm, 5 p.m) was used. The modifier was MeCN / EtOH 50:50 (20 to 50%), run for 6 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.Prep, chiral SFC 7: A ChiralPak IH column (30 x 250 mm, 5 gm) was used. The modifier was MeCN / EtOH 50:50 (45%), run for 3 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature postheater 35 °C, temperature preheater 40 °C, and temperature column department 40 °C.Prep, chiral SFC 8: A ChiralPak IB column (30 x 250 mm, 5 |im) was used. The modifier was MeOH (10%), run for 3.25 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.Prep, chiral SFC 9: A Chiralcel OX-H (30 x 250mm 5p.m) was used. The modifier was MeCN / EtOH 50:50 (40%), 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.Prep, chiral SFC 10: A Chiralcel OX-H (30 x 250mm 5p.m) was used. The modifier was MeCN / EtOH 50:50 (35%), 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.Prep, chiral SFC 11: A ChiralPak IC, (30 x 250mm 5p.m) was used. The modifier was MeCN / EtOH / DEA 50:50:0,1 (45%), run for 4 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.Prep, chiral SFC 12: A Chiralcel OX-H (30 x 250mm 5p.m) was used. The modifier was MeCN / EtOH 50:50 (30%), run for 8 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.Prep, chiral SFC 13: A Chiralcel OX-H (30 x 250mm 5p.m) was used. The modifier was MeCN / EtOH 50:50 (30%), run for 7.5 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.Prep, chiral SFC 14: A ChiralCel OZ-H column (30 x 250mm, 5um) was used. The modifier was EtOH, 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.Prep, chiral SFC 15: A Regis (R,R)-Whelk-O1 column (30 x 250 mm, 5 |im) was used. The modifier was MeCN / 2- PrOH 50:50 (35%), run for 4 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.Prep, chiral SFC 16: A ChiralPak AY-H column (30 x 250 mm, 5 |im) was used. The modifier was MeCN / EtOH 50:50 (40%), run for 4 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.Prep, chiral SFC 17: A ChiralPak IG column (30 x 250 mm, 5 gm) was used. The modifier was MeOH (20%), run for 6.5 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature preheater 40 °C, temperature postheater 35 °C, and temperature column department 40 °C.Prep, chiral SFC 18: A ChiralPak IH column (30 x 250 mm, 5 |im) was used. The modifier was MeOH (10%), run for 6 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature postheater 25 °C, temperature preheater 40 °C, and temperature column department 40 °C.Prep, chiral SFC 19'. A ChiralPak IG column (30 x 250 mm, 5 |im) was used. The modifier was MeOH (35%), run for 4 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature preheater 40 °C, temperature postheater 35 °C, and temperature column department 40 °C.Prep, chiral SFC 20: A ChiralPak IF column (30 x 250 mm, 5 |im) was used. The modifier was AcCN / EtOH / DEA 50:50:0.1 (40%), run for 4 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature preheater 40 °C, temperature postheater 35 °C, and temperature column department 40 °C.Prep, chiral SFC 21: A ChiralPak IF column (30 x 250 mm, 5 |im) was used. The modifier was AcCN / EtOH 50:50 (40%), run for 5 min and at a flow rate of 160 mL / min. The following system settings were used: backpressure 100 bar, temperature preheater 40 °C, temperature postheater 35 °C, and temperature column department 40 °C.HMNRBruker 500 MHz, Spectrometer Avance HD, 5mm DCH CyoprobeBruker 400 MHz, Spectrometer Avance II, 5 mm BBC probeheadFCFC (Flash Chromatography) was performed using a combiflash from Teledyne ISCO.Phase-separatorPhase separator cartriges used were Isolute® purchased from BiotageSolid Phase ExtractionIon exchange was performed using cationic exchange sorbent (Isolute® SXC) purchased from Biotage.Flow reactor for hydrogenation:H-Cube Pro from ThalesNano equipped with ThalesNano CatCart catalyst cartridde system, 30 mm LPreparation of Examples:Methods for the preparation of sulfonamides compounds (Examples 1.x)Example 1.1 (S)-11-(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide:((5-Chloro-2-methoxy-4-methylphenyl)sulfonyl)-L-proline: L-Proline (23.40 g, 0.20 mol, 1 eq) was dissolved in H2O (140 mL), then aq. 50% NaOH sin. (23.7 mL, 0.45 mol, 2.2 eq) was added. 5-Chloro-2-methoxy-4-methylbenzenesulfonyl chloride (50.90 g, 0.19 mol, 0.95 eq) was suspended in THF (90 mL) and added over 15 min to the mixture. The solvent was partially removed under reduced pressure. Aq. 25% HCI soln, was added to the colorless soln, to reach pH 1. DCM was added and the org. layer was washed with H2O. The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 0.87 min; [M+H]+: 334.2.Methyl ((5-chloro-2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate: BBrs (40.00 g, 0.16 mol, 2.5 eq) was dissolved in DCM (150 mL) and the soln, was cooled to 0°C. A soln, of ((5-chloro-2-methoxy-4- methylphenyl)sulfonyl)-L-proline (106.00 g, 0.064 mol, 1 eq) in DCM (110 mL) was slowly added and the soln, stirred for 1 h at 0°C. The soln, was cooled down to 0°C and MeOH (38.6 mL, 0.96 mol, 15 eq) was slowly added and stirred for 5h. H2O was added followed by aq. sat. Na2CO3 soln.. The layers were separated. The org. layer was washed with aq. 1 M Na2CO3 soln, and with aq. 1 M HCI soln., dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 0.87 min; [M+H]+: 334.2.Methyl ((2-(benzyloxy)-5-chloro-4-methylphenyl)sulfonyl)-L-prolinate: Methyl ((5-chloro-2-hydroxy-4- methylphenyl)sulfonyl)-L-prolinate (22.50 g, 0.067 mol, 1 eq) was dissolved in DMF (94 mL) and K2COs (14.00 g, 0.10 mol, 1.5 eq) was added followed by benzyl bromide (7.9 mL, 0.065 mol, 1 eq). The mixture was heated to 45°C and stirred for 1h. The mixture was cooled down to rt and H2O was added. The mixture was diluted with / PrOAc. The org. layer was separated and washed with aq. sat. NaHCO3 soln, and H2O. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 1.07 min; [M+H]+: 424.3.((2-(Benzyloxy)-5-chloro-4-methylphenyl)sulfonyl)-L-proline: Methyl ((2-(benzyloxy)-5-chloro-4- methylphenyl)sulfonyl)-L-prolinate (30.40 g, 0.072 mol, 1 eq) was dissolved in MeOH (130 mL) and aq. 32% NaOH soln. (13.3 mL, 0.14 mol, 2 eq) in H2O (440 mL) was then added. The mixture was stirred at rt for 1 h and aq. 32% NaOH soln. (7 mL) was added again and the mixture was stirred for 40 min. The mixture was extracted with DCM. The org. layer was washed with aq. 1 M HCI soln. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compond. LC-MS (1): tR= 0.97 min; [M+H]+: 410.3. tert-Butyl ((2-(benzyloxy)-5-chloro-4-methylphenyl)sulfonyl)-L-prolinate: tBuOH (40.70 g, 0.55 mol, 7.5 eq) was dissolved in 2-MeTHF (209 mL). Then ((2-(benzyloxy)-5-chloro-4-methylphenyl)sulfonyl)-L-proline (30.00 g, 0.073 mol, 1 eq) was added followed by DMAP (1.79 g, 0.015 mol, 0.2 eq). A soln, of Boc2O (22.40 g, 0.10 mol, 1.4 eq) in 2-MeTHF (104 mL) was added dropwise and the soln, was stirred for 30 min at rt. Imidazole (2.49 g, 0.037 mol, 0.5 eq) was added and the mixture was stirred for 30 min. Aq. 1 M HCI soln, was slowly added and the layers were separated. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent removed under reduced pressure. To the residue, tBME (250 mL) was added forming a precipitate. Hept, was added and the suspension was vigorously stirred for 30 min, filtered, and washed with Hept. The solid was dried under reduced pressure to give the title compound. LC-MS (1): tR= 1.16 min; [M+H]+: 466.2.fert-Butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate: fert-Butyl ((2-(benzyloxy)-5-chloro-4- methylphenyl)sulfonyl)-L-prolinate (25.00 g, 0.054 mol, 1 eq) and sodium acetate anhydrous (8.74 g, 0.11 mol, 2 eq) were suspended in MeOH (110 mL). Pd(OH)2 / C (20 wt. %, wet, 4.00 g, 0.006 mol, 0.1 eq) was added and the mixture was heated at 50°C under a H2atm. overnight. The mixture was then filtered and washed with MeOH. The filtrate was evaporated under reduced pressure and the residue was dissolved in tBME and washed with aq. sat. NaHCO3 soln., aq. 1 M HCI soln., and H2O to give the title compound. LC-MS (1): IR= 0.95 min; [M+H]+: 342.3.N-(5-((fert-Butyldimethylsilyl)oxy)pentyl)-4,4-difluorocyclohexan-1-amine: 4,4-Difluorocydohexan-1-amine (600 mg, 4.31 mmol, 1 eq) was dissolved in THF (40 mL). 5-[(tert-Butyldimethylsilyl)oxy]pentanal (1.03 g, 4.52 mmol, 1 .05 eq) in THF (10 mL) was added at rt followed by AcOH (0.25 mL, 4.31 mmol, 1 eq). The mixture was stirred for 30 min, then NaBH(OAc)3(1.44 g, 6.46 mmol, 1.5 eq) was added and the mixture was stirred at rt overnight. The reaction was poured into aq. sat. NaHCO3soln, and extracted with EtOAc. The org. layer was washed once with H2O, dried over MgSCU, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound.1H NMR (500 MHz, CDCL) 3: 0.06 (s, 6 H), 0.91 (s, 9 H), 1.36-1.42 (m, 2 H), 1.51-1.67 (m, 6 H), 1.71-1.84 (m, 2 H), 1.99-2.03 (m, 3 H), 2.16 (m, 2 H), 2.73 (m, 2 H), 2.79 (t, J = 9.9 Hz, 1 H), 3.62 (t, J = 6.4 Hz, 2 H). fert-Butyl (5-((fert-butyldimethylsilyl)oxy)pentyl)(4,4-difluorocyclohexyl)carbamate: N-(5-((fert-Butyldimethylsilyl)oxy)pentyl)-4,4-difluorocyclohexan-1-amine (660 mg, 1.97 mmol, 1 eq) and TEA (0.68 mL, 4.92 mmol, 2.5 eq) were dissolved in DCM (40 mL). The mixture was cooled to 0°C and Boc2O (520 mg, 2.36 mmol, 1.2 eq) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was partitioned between DCM and brine. The org. layer was washed with brine. The org. layer was separated through a phase separator cartridge and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.30 min; [M+H]+: 436.3. fert-Butyl (4,4-difluorocyclohexyl)(5-hydroxypentyl)carbamate: fert-Butyl (5-((fert- butyldimethylsilyl)oxy)pentyl)(4,4-difluorocyclohexyl)carbamate (351 mg, 0.81 mmol, 1 eq) was dissolved in THF (10 mL). TBAF.3H2O (254 mg, 0.81 mmol, 1 eq) was added dropwise at 0°C. The reaction was then allowed to stir at rt overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with H2O and brine. The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 0.95 min; [M+H]+: 322.1. fert-Butyl ((2-((5-((fert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentyl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate: A soln, of tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate (175 mg, 0.51 mmol, 1 eq) in THF (8 mL) was cooled to 0°C. tert-butyl (4,4-difluorocyclohexyl)(5- hydroxypentyl)carbamate (214 mg, 0.67 mmol, 1.3 eq) and PPh3(177 mg, 0.67 mmol, 1 .3 eq) were added followed by DEAD (-40% in toluene, 0.60 mL, 1.23 mmol, 2.4 eq). After the addition, the mixture was allowed to warm up to rt and stirred for 72h. The solvent was removed under reduced pressure and the residue was taken up in Et2O andfiltered. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.23 min; [M+H]+: 645.3.((2-((5-((4,4-Difluorocyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-proline: fert-Butyl ((2-((5- ((fert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate (240 mg, 0.37 mmol, 1 eq) was dissolved in DCM (10 mL). TFA (2.0 mL, 26.10 mmol, 70 eq) was added at rt and the resulting mixture was stirred for 1 h. The solvent was removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.23 min; [M+H]+: 489.2.(S)-11-(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-benzo[b]pyrrolo[1,2- e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: ((2-((5-((4,4-Difluorocyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-proline (417 mg, 0.85 mmol, 1 eq) was dissolved in DMF (12 mL). DIPEA (1.2 mL, 6.82 mmol, 8 eq) and HATU (389 mg, 1.02 mmol, 1.2 eq) were added at rt and the mixture was stirred at rt for 5 min. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.01 min; [M+H]+: 471.2.Example 1.2 (6S,10aS)-9-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10a,11,12,13-octahydro-10H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacycloundecin-10-one 15,15-dioxide:(R)-N-(3-((fert-Butyldimethylsilyl)oxy)butyl)-4,4-difluorocyclohexan-1-amine: 4,4-Difluorocyclohexan-1-amine (220 mg, 1.58 mmol, 1 eq) was dissolved in THF (40 mL) and (R)-3-((fert-butyldimethylsilyl)oxy)butanal (W02016208602 A1) (335 mg, 1.66 mmol, 1.05 eq) in THF (10 mL) was added at rt followed by AcOH (0.09 mL, 1.58 mmol, 1 eq). The mixture was stirred for 30 min, then NaBH(OAc)3 (528 mg, 2.37 mmol, 1.5 eq) was added and the mixture was stirred at rt overnight. The reaction mixture was poured into aq. sat. NaHCO3 soln, and extracted with EtOAc. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound.1H NMR (500 MHz, CDCI3) δ: 0.07 (d, J = 4.4 Hz, 6 H), 0.90 (s, 9 H), 1.17 (d, J = 6.1 Hz, 3 H), 1.60-1.87 (m, 5 H), 2.00-2.03 (m, 4 H), 2.13-2.19 (m, 2 H), 2.77-2.88 (m, 3 H), 3.91-3.95 (m, 1 H). fert-Butyl (R)-(3-((fert-butyldimethylsilyl)oxy)butyl)(4,4-difluorocyclohexyl)carbamate: (R)-N-(3-((fert- Butyldimethylsilyl)oxy)butyl)-4,4-difluorocyclohexan-1 -amine (308 mg, 0.96 mmol, 1 eq) and TEA (0.33 mL, 2.39 mmol, 2.5 eq) were dissolved in DCM (40 mL). The mixture was cooled to 0°C and BOC2O (253 mg, 1.15 mmol, 1.2 eq) was added and the mixture was stirred at rt overnight. The reaction mixture was partitioned between DCM and brine. The org. layer was washed with brine. The org. layer was separated through a phase separator cartridge and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 1.27 min; [M+H]+: 422.3. fert-Butyl (R)-(4,4-difluorocyclohexyl)(3-hydroxybutyl)carbamate: fert-Butyl (R)-(3-((fert- butyldimethylsilyl)oxy)butyl)(4,4-difluorocyclohexyl)carbamate (288 mg, 0.68 mmol, 1 eq) was dissolved in THF (14 mL). TFA.3H2O (216 mg, 0.68 mmol, 1 eq) was added dropwise at 0°C. The reaction was then allowed to stir at rt for 1h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed withH2O and brine. The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure to give the title compound. The crude product was used without further purification in the next step. LC-MS (1): IR= 0.96 min; [M+H]+: 308.3. tert- Butyl ((2-(((S)-4-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)butan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate: Was synthesized using tert-butyl (R)-(4,4-difluorocyclohexyl)(3- hydroxybutyl)carbamate and tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 1.22 min; [M+H]+: 631.3.((2-(((S)-4-((4,4-Difluorocyclohexyl)amino)butan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline: Was synthesized using tert-butyl ((2-(((S)-4-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)butan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 0.72 min; [M+H]+: 475.2.(6S,10aS)-9-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10a,11,12,13-octahydro-10H-benzo[b]pyrrolo[1,2- e][1]oxa[4]thia[5,8]diazacycloundecin-10-one 15,15-dioxide: Was synthesized using ((2-(((S)-4-((4,4- difluorocyclohexyl)amino)butan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 0.98 min; [M+H]+: 457.3.Example 1.3 (6R,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:(S)-N-(4-((tert-Butyldimethylsilyl)oxy)pentyl)-4,4-difluorocyclohexan-1-amine: 4,4-Difluorocyclohexan-1- amine (415 mg, 2.98 mmol, 1 eq) was dissolved in THF (7 mL). Then (S)-4-((tert-butyldimethylsilyl)oxy)pentanal (J. Org. Chem. (2004), 69(3), 891-898) (335 mg, 1.66 mmol, 1.05 eq) in THF (10 mL) was added at rt, followed by AcOH (0.17 mL, 2.98 mmol, 1 eq). The mixture was stirred for 30 min, then NaBH(OAc)3 (821 mg, 3.87 mmol, 1.3 eq) was added and the mixture was stirred at rt overnight. The reaction mixture was poured into aq. sat. NaHCO3 soln, and extracted with EtOAc. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent was removed, under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound.1H NMR (500 MHz, CDCI3) δ: 0.07 (d, J = 2.6 Hz, 6 H), 0.91 (s, 9 H), 1.15 (d, J = 6.1 Hz, 3 H), 1.40- 1.84 (m, 9 H), 1.89-1.93 (m, 2 H), 2.07-2.20 (m, 2 H), 2.61-2.64 (m, 3 H), 3.80-3.84 (m, 1 H). tert-Butyl (S)-(4-((fert-butyldimethylsilyl)oxy)pentyl)(4,4-difluorocyclohexyl)carbamate: (S)-N-(4-((fert- Butyldimethylsilyl)oxy)pentyl)-4,4-difluorocyclohexan-1-amine (579 mg, 1.73 mmol, 1 eq) and TEA (0.60 mL, 4.31 mmol, 2.5 eq) were dissolved in DCM (40 mL). The mixture was cooled to 0°C and Boc2O (456 mg, 2.07 mmol, 1.2 eq) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was partitioned between DCM and brine. The org. layer was washed with brine. The org. layer was separated through a phase separator cartridge and the solvent was removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 1.31 min; [M+H]+: 436.4.fert-Butyl (S)-(4,4-difluorocyclohexyl)(4-hydroxypentyl)carbamate: fert-Butyl (S)-(4-((fert- butyldimethylsilyl)oxy)pentyl)(4,4-difluorocyclohexyl)carbamate (350 mg, 0.80 mmol, 1 eq) was dissolved in THF (25 mL). TFA.3H2O (259 mg, 0.82 mmol, 1 .02 eq) was added dropwise at 0°C. The reaction was then allowed to stir at rt for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with H2O and brine. The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure. LC-MS (1): tR= 0.94 min; [M+H]+: 322.2. tert- Butyl ((2-(((R)-5-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate: Was synthesized using tert-butyl (S)-(4,4-difluorocyclohexyl)(4- hydroxypentyl)carbamate and tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 1.24 min; [M+H]+: 645.4.((2-(((R)-5-((4,4-Difluorocyclohexyl)amino)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline: Was synthesized using tert-butyl ((2-(((R)-5-((fert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 0.73 min; [M+H]+: 489.0.(6R,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydrobenzo[b]pyrrolo[1,2- e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using ((2-(((R)-5-((4,4- difluorocyclohexyl)amino)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 1.02 min; [M+H]+: 471.3.Example 1.4 (6S,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using (R)-4-((fert-butyldimethylsilyl)oxy)pentanal (Chemistry Asian J. (2013), 8(7), 1391-1394) in analogy to Example 1.3 to give the title compound. LC-MS (1): tR= 1.03 min; [M+H]+: 471.3.Example 1.5 (6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14,15-octahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: tert- Butyl ((4-methyl-2-(((S)-pent-4-en-2-yl)oxy)phenyl)sulfonyl)-L-prolinate: fert-Butyl ((2-hydroxy-4- methylphenyl)sulfonyl)-L-prolinate (160 mg, 0.47 mmol, 1 eq) was dissolved in THF (9 mL). The soln, was cooled to 0°C. Then (2R)-pent-4-en-2-ol (55 mg, 0.61 mmol, 1.3 eq) and PPhs (162 mg, 0.61 mmol, 1.3 eq) were added followed by DEAD (-40% in toluene, 0.55 mL, 1.13 mmol, 2.4 eq). After the addition, the mixture was allowed to warm up to rt and stirred overnight. After this time Et2O was added and the mixture was filtered. The solvent was removed under reduced pressure and the residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 1.13 min; [M+H]+: 410.3.((4-Methyl-2-(((S)-pent-4-en-2-yl)oxy)phenyl)sulfonyl)-L-proline: fert-Butyl ((4-methyl-2-(((S)-pent-4-en-2- yl)oxy)phenyl)sulfonyl)-L-prolinate (80 mg, 0.20 mmol, 1 eq) was dissolved in DCM (6 mL). TFA (1.1 mL, 13.70 mmol, 70 eq) was added at rt and the resulting mixture was stirred at rt for 2h. The solvent was removed underreduced pressure and the residue was used without further purification in the next step. LC-MS (1): IR= 0.90 min; [M+H]+: 354.2.N-Allyl-4,4-difluorocyclohexan-1-amine: 4,4-Difluorocyclohexanone (600 mg, 4.29 mmol, 1 eq) was dissolved in THF (25 mL). Allylamine (0.34 mL, 4.51 mmol, 1.05 eq) in THF (5 mL) was added at rt followed by AcOH (0.25 mL, 4.29 mmol, 1 eq). The mixture was stirred for 30 min, then NaBH(OAc)3 (1 .44 g, 6.44 mmol, 1.5 eq) was added and the mixture was stirred at rt overnight. Aq. 10% Na2CO3 soln, was added and the mixture was extracted with EtOAc. The aq. layer was basified with aq. 1 M NaOH soln., and extracted with EtOAc.The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (EtOAc to 10% MeOH) to give the title compound. LC-MS (1): IR= 0.47 min; [M+H]+: 176.4.(S)-N-Allyl-N-(4,4-difluorocyclohexyl)-1-((4-methyl-2-(((S)-pent-4-en-2-yl)oxy)phenyl)sulfonyl)pyrrolidine-2- carboxamide: ((4-Methyl-2-(((S)-pent-4-en-2-yl)oxy)phenyl)sulfonyl)-L-proline (80 mg, 0.23 mmol, 1 eq) was dissolved in DMF (1 mL). DIPEA (0.12 mL, 0.68 mmol, 3 eq), PyCloP (117 mg, 0.27 mmol, 1.2 eq) and N-allyl-4,4- difluorocyclohexan-1 -amine (55.5 mg, 0.32 mmol, 1.4 eq) were added. The mixture was stirred at rt overnight. The soln, was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.13 min; [M+H]+: 410.3.(6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14,15-octahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: (S)-N-allyl-N-(4,4- difluorocyclohexyl)-1-((4-methyl-2-(((S)-pent-4-en-2-yl)oxy)phenyl)sulfonyl)pyrrolidine-2-carboxamide (30 mg, 0.059 mmol, 1 eq) was dissolved in DCM (1 mL) under N2 atm. Grubbs Catalyst, 2nd generation (1.3 mg, 47 pimol, 0.025 eq) was added and the soln, was stirred at 45°C for 1h. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.02 min; [M+H]+: 483.3.Example 1.6 (6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: (6S,12aS)-11-(4,4- Difl uorocydohexy l)-3, 6-di methyl-6, 7, 10, 11 , 12a, 13, 14, 15-octahydro-12H-benzo[b]pyrrolo[1 ,2-e]

[0001] oxa[4]th i a[5, 8] diazacyclotridecin-12-one 17,17-dioxide (20 mg, 0.041 mmol, 1 eq) was dissolved in EtOH (2 mL). The reaction flask was purged with N2and 10% Pd / C (1 mg) was added. The reaction mixture was stirred under a H2atm at rt for 1 h. The mixture was filtered over a Celite pad and washed with EtOH. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.04 min; [M+H]+: 485.3.Example 1.7 (S)-11-(4,4-Dimethylcyclohexyl)-3-methyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: tert- Butyl ((2-((5-hydroxypentyl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate: At 0°C and under a N2 atm, DEAD (-40% in toluene, 1 .4 mL, 2.93 mmol, 2 eq) was added to a stirred soln, of 1 ,5-pentanediol (0.80 mL, 7.32 mmol, 5 eq) and PPhs (468 mg, 1.76 mmol, 1.2 eq) in THF (17 mL). The mixture was stirred for 10 min. A soln, of tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate (500 mg, 1.46 mmol, 1 eq) in THF (6 mL) was added dropwiseand the reaction was stirred at rt for 1 h. The reaction mixture was diluted with Et20 and washed with aq. 1 M HCI soln., aq. sat. NaHCO3Soln., and H2O. The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to 5% MeOH) to give the title compound. LC-MS (1): tR= 0.98 min; [M+H]+: 428.1. tert- Butyl ((4-methyl-2-((5-oxopentyl)oxy)phenyl)sulfonyl)-L-prolinate: At -78°C under N2 atm, DMSO (0.13 mL, 1.85 mmol, 2.7 eq) was added dropwise to a stirred soln, of oxalyl chloride (0.09 mL, 1.03 mmol, 1.5 eq) in DCM (10 mL). The mixture was stirred at -78°C for 10 min, then a soln, of tert-butyl ((2-((5-hydroxypentyl)oxy)-4- methylphenyl)su lfonyl)-L-prol i n ate (293 mg, 0.69 mmol, 1 eq) in DCM (4 mL) was added dropwise. After stirring for another 10 min, Et3N (0.50 mL, 3.43 mmol, 5 eq) was added dropwise. The reaction was stirred at -78°C for another 15 min and then allowed to slowly warm up to -20°C. Aq. 1 M HCI soln, was added and the mixture was extracted with Et20. The org. layer was washed with aq. sat. NaHCO3soln, and H2O, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): tR= 1.03 min; [M+H]+: 426.1. tert-Butyl ((2-((5-((4,4-dimethylcyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate: At rt, NaBH(OAc)3 (32 mg, 0.14 mmol, 1.5 eq) was added to a soln, of tert-butyl ((4-methyl-2-((5- oxopentyl)oxy)phenyl)sulfonyl)-L-prolinate (40 mg, 0.09 mmol, 1 eq) and 4,4-dimethylcyclohexan-1-amine (20 μL, 0.11 mmol, 1.2 eq) in THF (1 mL) and the reaction mixture was stirred at rt overnight. The reaction was poured onto aq. sat. NaHCO3soln, and extracted with DCM. The layers were separated by phase separator and the org. layer was evaporated under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 0.95 min; [M+H]+: 537.5.((2-((5-((4,4-Dimethylcyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-proline: At rt, tert-butyl ((2- ((5-((4,4-dimethylcyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate (40 mg, 0.075 mmol, 1 eq) was dissolved in DCM (2 mL), then TFA (0.11 mL, 1 .49 mmol, 20 eq) was added and the mixture was stirred at rt for 6h. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step. LC-MS (1): tR= 0.82 min; [M+H]+: 481.1.(S)-11 -(4,4-Dimethylcyclohexyl)-3-methyl-6,7,8,9, 10, 11 , 12a, 13, 14, 15-decahydro-12H-benzo[b]pyrrolo[1 ,2- e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: At rt, HATU (32 mg, 0.082 mmol, 1.1 eq) and DIPEA (32 μL, 0.19 mmol, 2.5 eq) were added to a stirred soln, of ((2-((5-((4,4- dimethylcyclohexyl)amino)pentyl)oxy)-4-methylphenyl)sulfonyl)-L-proline (42 mg, 0.075 mmol, 1 eq) in DMF (2 mL) and the soln, was stirred at rt for 30 min. The soln, was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.13 min; [M+H]+: 463.1.Example 1.8 (S)-11 -(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9, 10, 11 , 12a, 13, 14, 15-decahydropyrido[2,3- l]pyrrolo[1,2-b][1]thia[2,5,11]triazacyclotridecin-12(5H)-one 17,17-dioxide:Methyl ((2-chloro-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: L-Proline methyl ester hydrochloride (5.10 g, 30.50 mmol, 1 eq) was dissolved in DCM (120 mL). DIPEA (15.7 mL, 91.50 mmol, 3 eq) and DMAP (372 mg, 3.05mmol, 0.1 eq) were added at it The reaction was cooled to 0°C and 2-chloro-6-methylpyridine-3-sulfonyl chloride (7.47 g, 31 .40 mmol, 1 .03 eq) was added. The mixture was stirred at rt overnight. The mixture was quenched with aq. sat. NaHCO3soln, and extracted with DCM. The org. layer was washed once with H2O, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 0.81 min; [M+H]+: 319.1.((2-Chloro-6-methylpyridin-3-yl)sulfonyl)-L-proline: Methyl ((2-chloro-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (5.00 g, 15.70 mmol, 1 eq) was dissolved in THF (120 mL) and aq. 1 M LiOH soln. (47.1 mL, 47.10 mmol, 3 eq) was added. The soln, was stirred during 1h at rt. The mixture was quenched with aq. 2M HCI soln, until pH 1 and extracted with EtOAc. The combined org. layers were dried oved MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): tR= 0.67 min; [M+H]+: 305.1.((2-(Allylamino)-6-methylpyridin-3-yl)sulfonyl)-L-proline: ((2-Chloro-6-methylpyridin-3-yl)sulfonyl)-L-proline (620 mg, 2.03 mmol, 1 eq) and allylamine (0.46 mL, 6.10 mmol, 3 eq) were dissolved in TMP (2 mL) and the reaction mixture was stirred at 90°C for 8 days. The reaction mixture was cooled down to rt. The soln, was purified by acidic prep. HPLC to give the title compound. LC-MS (1): tR= 0.75 min; [M+H]+: 326.3.N-(But-3-en-1-yl)-4,4-difluorocyclohexan-1-amine: 4,4-Difluorocyclohexanone (600 mg, 4.29 mmol, 1 eq) was dissolved in THF (25 mL). 3-Buten-1 -amine (327 mg, 4.51 mmol, 1.05 eq) in THF (5 mL) was added followed by AcOH (0.25 mL, 4.29 mmol, 1 eq). The mixture was stirred for 30 min, then NaBH(OAc)3 (1.44 g, 6.44 mmol, 1.5 eq) was added and the mixture was stirred at rt overnight. The reaction was poured into aq. sat. NaHCO3soln, and extracted with EtOAc. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (EtOAc to 10% MeOH) to give the title compound. LC-MS (1): tR= 0.48 min; [M+H]+: 190.4.(S)-1-((2-(Allylamino)-6-methylpyridin-3-yl)sulfonyl)-N-(but-3-en-1-yl)-N-(4,4- difluorocyclohexyl)pyrrolidine-2-carboxamide: ((2-(Allylamino)-6-methylpyridin-3-yl)sulfonyl)-L-proline (100 mg, 0.31 mmol, 1 eq) was dissolved in DMF (1 mL). DIPEA (0.16 mL, 0.92 mmol, 3 eq), PyCloP (159 mg, 0.37 mmol, 1.2 eq) and N-(but-3-en-1-yl)-4,4-difluorocyclohexan-1 -amine (64 mg, 0.34 mmol, 1.1 eq) were added. The mixture was stirred at rt overnight. The soln, was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.05 min; [M+H]+: 497.2.(S)-11-(4,4-Difluorocyclohexyl)-3-methyl-6,9,10,11,12a,13,14,15-octahydropyrido[2,3-l]pyrrolo[1,2- b][1]thia[2,5,11]triazacyclotridecin-12(5H)-one 17,17-dioxide: (S)-1-((2-(Allylamino)-6-methylpyridin-3- yl)sulfonyl)-N-(but-3-en-1-yl)-N-(4,4-difluorocyclohexyl)pyrrolidine-2-carboxamide (96 mg, 0.19 mmol, 1 eq) was dissolved in THF (5 mL) and Hoveyda-Grubbs Catalyst (18 mg, 0.029 mmol, 0.15 eq) was added. The soln, was degassed with a N2flow and stirred at 65°C for 1h. Hoveyda-Grubbs Catalyst (18 mg, 0.029 mmol, 0.15 eq) was added again and the reaction mixture was stirred at 65°C overnight. The mixture was cooled to rt and the solventwas removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 0.89 min; [M+H]+: 469.3.(S)-11-(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9,10,11,12a,13,14,15-decahydropyrido[2,3-l]pyrrolo[1,2- b][1]thia[2,5,11]triazacyclotridecin-12(5H)-one 17,17-dioxide: (S)-11-(4,4-Difluorocyclohexyl)-3-methyl- 6,9, 10, 11 , 12a, 13, 14, 15-octahydropy rido[2, 3-l]py rrolo[ 1 ,2-b]

[0001] thia[2, 5, 11 ]triazacyclotridecin-12(5H)-one 17,17- dioxide (36 mg, 0.077 mmol, 1 eq) was dissolved in EtOH (1 mL). The reaction flask was purged with N2and 10% Pd / C (1 mg) was added. The reaction was stirred under H2atm for 1h. The mixture was filtered and washed with EtOH. The solvent was removed under reduced pressure and the residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 0.90 min; [M+H]+: 471.0.Example 1.9 (S)-5-(4,4-Difluorocyclohexyl)-13-methyl-1,2,3,3a,6,7,8,9-octahydrobenzo[l]pyrrolo[1,2- b][1]thia[2,5]diazacyclotridecin-4(5H)-one 16, 16-dioxide: tert- Butyl ((2-bromo-4-methylphenyl)sulfonyl)-L-prolinate: TEA (2.9 mL, 21.10 mmol, 2 eq) was added dropwise to a soln, of 2-bromo-4-methylbenzene-1 -sulfonyl chloride (3.00 g, 10.60 mmol, 1 eq) and L-proline t-butyl ester (2.0 mL, 11.60 mmol, 1.1 eq) in DCM (75 mL) at 0°C. The reaction was stirred at rt overnight. The reaction mixture was diluted with aq. sat. NaHCO3soln, and the layers were separated. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound. LC-MS (1): tR= 1.06 min; [M+H]+: 405.9. tert-Butyl ((4-methyl-2-vinylphenyl)sulfonyl)-L-prolinate: A soln. of tert-butyl ((2-bromo-4- methylphenyl)sulfonyl)-L-prolinate (215 mg, 0.53 mmol, 1 eq), 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (129 mg, 0.80 mmol, 1.5 eq), (dppf)PdCI2CH2CI2(43 mg, 0.053 mmol, 0.1 eq) and K2CO3(220 mg, 1.60 mmol, 3 eq) in dioxane / H2O (4: 1 , 5 mL)was degassed for 15 min and stirred at 90°C over the weekend. The reaction mixture was diluted with aq. 1 M HCI soln, and EtOAc. The layers were separated and the org. layer was washed with aq. sat. NaHCO3soln., H2O, and brine. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 1.06 min; [M+H]+: 352.3.((4-Methyl-2-vinylphenyl)sulfonyl)-L-proline: TFA (0.40 mL, 5.69 mmol, 10 eq) was added to a soln, of tert-butyl ((4-methyl-2-vinylphenyl)sulfonyl)-L-prolinate (200 mg, 0.57 mmol, 1 eq) in DCM (3 mL) and the mixture was stirred at rt for 1.5h. The solvent was removedunder reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): tR= 0.82 min; [M+H]+: 296.2.4,4-Difluoro-N-(hex-5-en-1-yl)cyclohexan-1-amine: A soln, of 4,4-difluorocyclohexanone (300 mg, 2.15 mmol, 1 eq), 1-amino-5-hexene (247 mg, 2.36 mmol, 1.1 eq) and AcOH (0.12 mL, 2.15 mmol, 1 eq) in THF (10 mL) was stirred at rt for 30 min. Then, NaBH(OAc)3(719 mg, 3.22 mmol, 1.5 eq) was added and the mixture was stirred at rt overnight. The reaction was poured into aq. sat. NaHCO3soln, and extracted with EtOAc. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): tR= 0.62 min; [M+H]+: 218.3.(S)-N-(4,4-Difluorocyclohexyl)-N-(hex-5-en-1-yl)-1-((4-methyl-2-vinylphenyl)sulfonyl)pyrrolidine-2- carboxamide: DIPEA (0.40 mL, 2.29 mmol, 4 eq) was added to a soln, of ((4-methyl-2-vinylphenyl)sulfonyl)-L- proline (169 mg, 0.57 mmol, 1 eq) and HATU (269 mg, 0.69 mmol, 1.2 eq) in DMF (2 mL). The yellow soln, was stirred for 10 min at rt and a soln, of 4,4-difluoro-N-(hex-5-en-1-yl)cyclohexan-1 -amine (137 mg, 0.63 mmol, 1.1 eq) in DMF (0.5 mL) was added. The mixture was stirred at rt overnight. The reaction mixture was purified by acidic prep. HPLC to give the title compound. LC-MS (1): IR= 1.14 min; [M+H]+: 495.3.(S)-5-(4,4-Difluorocyclohexyl)-13-methyl-1,2,3,3a,6,7,8,9-octahydrobenzo[l]pyrrolo[1,2- b][1]thia[2,5]diazacyclotridecin-4(5H)-one 16, 16-dioxide: A soln, of (S)-N-(4,4-difluorocyclohexyl)-N-(hex-5-en- 1-yl)-1-((4-methyl-2-vinylphenyl)sulfonyl)pyrrolidine-2-carboxamide (19 mg, 0.038 mmol, 1 eq) in toluene (1 mL) was evacuated and purged with N2 atm. Grubbs Catalyst, 2nd generation (2 mg, 19 pimol, 0.05 eq) was added and the mixture was stirred at 110°C for 1h. The solvent was removed under reduced pressure and the residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): IR= 1.10 min; [M+H]+: 467.0.Example 1.10 to Example 1.11 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((2-((5-hyd roxypenty l)oxy)-4-methy I phenyl)sulfony l)-L-prol i nate in analogy to Example 1 .7. LC-MS data of Example 1.10 to Example 1.11 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.12 (S)-5-(4,4-Difluorocyclohexyl)-13-methyl-1,2,3,3a,6,7,8,9,10,11-decahydrobenzo[l]pyrrolo[1,2- b][1]thia[2,5]diazacyclotridecin-4(5H)-one 16, 16-dioxide: A mixture of (S, -5-(4,4-difluorocyclohexyl)-13-methyl- 1 , 2, 3, 3a, 6, 7, 8, 9-octahyd robenzo[l]pyrrolo[ 1 , 2-b]

[0001] thi a[2, 5]di azacyclotrideci n-4(5 H )-one 16, 16-dioxide (77 mg, 0.17 mmol, 1 eq) was dissolved in EtOH (5 mL). The reaction flask was purged with N2 and 10% Pd / C (10 mg, 94 pimol, 0.06 eq) was added and the reaction mixture was stirred under a H2 atm at rt for 1 h. The mixture was filtered over a Celite pad and washed with EtOH. The solvent was removed under reduced pressure and the residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): IR= 1.12 min; [M+H]+: 469.3.Example 1.13 (6R,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro- 12H-benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: Was synthesized using tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate and (2S)-pent-4-en-2-ol in analogy to Example 1.6 to give the title compound. LC-MS (1): tR= 1.05 min; [M+H]+: 485.0.Example 1.14 (6RS,11aS)-10-(1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide:(RS)-5-((tert-Butyldimethylsilyl)oxy)pentan-2-ol: At rt, a soln, of tert-butyl(chloro)dimethylsilane (1.59 g, 10.00 mmol, 1 eq) in DCM (10 mL) was added dropwise to a stirred soln, of 1 ,4-pentanediol (1.0 mL, 10.00 mmol, 1 eq) and imidazole (1.38 g, 20.00 mmol, 2 eq) in DCM (40 mL) within 1h. The reaction was stirred for 30 min. The mixture was diluted with DCM and washed with aq. 1 M HCI soln, and H2O. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used without further purification in the next step.1H NMR (500 MHz, CDCI3) δ: 3.83-3.84 (m, 1 H), 3.65-3.72 (m, 2 H), 2.63 (s, 1 H), 1.59-1.70 (m, 3 H), 1.45-1.58 (m, 1 H), 0.91-0.94 (m, 10 H), 0.09 (m, 6 H). tert- Butyl ((2-(((RS)-5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate: Was synthesized using tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate and (RS)-5-((fert- Butyldimethylsilyl)oxy)pentan-2-ol in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 1.30 min; [M+H]+: 542.0. tert-Butyl ((2-(((RS)-5-hydroxypentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate: tert-Butyl ((2-(((RS)-5- ((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate (2.34 g, 4.32 mmol, 1 eq) was dissolved in THF (45 mL). Then 1 M TBAF soln, in THF (5.2 mL, 5.18 mmol, 1.2 eq) was added at once and the soln, was stirred at rt for 2h. The reaction was diluted with Et20 and washed with H2O. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (DCM to 5% MeOH) to give the title compound. LC-MS (1): tR= 0.97 min; [M+H]+: 428.1. tert-Butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)oxy)phenyl)sulfonyl)-L-prolinate: Was synthesized using tert- butyl ((2-(((RS)-5-hydroxypentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.7 to give the title compound. LC-MS (1): tR= 1.04 min; [M+H]+: 426.3. tert-Butyl ((2-(((RS)-5-((1,1-difluorospiro[2.3]hexan-5-yl)amino)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)- L-prolinate: Was synthesized using tert-butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)oxy)phenyl)sulfonyl)-L- prolinate and 1 , 1-difluorospiro[2.3]hexan-5-amine hydrochloride in analogy to Example 1.7 to give the title compound. LC-MS (1): tR= 0.90 and 0.91 min; [M+H]+: 543.0.((2-(((RS)-5-((1,1-Difluorospiro[2.3]hexan-5-yl)amino)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline: Was synthesized using tert-butyl ((2-(((RS)-5-((1 , 1-difluorospiro[2.3]hexan-5-yl)amino)pentan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.7 to give the title compound. LC-MS (1): tR= 0.75 and 0.76 min; [M+H]+: 487.0.(6RS,11aS)-10-(1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using ((2-(((RS)-5-((1 , 1-difluorospiro[2.3]hexan-5-yl)amino)pentan-2-yl)oxy)-4-methylphenyl)sulfonyl)- L-proline in analogy to Example 1.7 to give the title compound. LC-MS (1): tR= 1.03 min; [M+H]+: 469.3.Example 1.15 to Example 1.21 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)oxy)phenyl)sulfonyl)-L-prolinate in analogy to Example 1.14. LC-MS data of Example 1 .15 to Example 1 .21 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.22 (S)-11 -(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9, 10, 11 , 12a, 13, 14, 15-decahydro-12H- pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide:5-((3-Bromo-6-methylpyridin-2-yl)oxy)pentan-1-ol: DEAD (~ 40% in toluene, 9.40 mL, 20.40 mmol, 2 eq) was added dropwise to a stirred soln, of 3-bromo-6-methylpyridin-2-ol (2.00 g, 10.20 mmol, 1 eq), 1,5-pentanediol (5.60 mL, 51.10 mmol, 5 eq) and PPha (3.25 g, 12.30 mmol, 1.2 eq) in THF (50 mL) at 0°C under N2 atm. The reaction was warmed to rt and stirred for 3h. The reaction was diluted with Et20 and washed with brine. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 0.90 min; [M+H]+: 276.1.3-Bromo-2-((5-((fert-butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine: A soln. of tert- butyl(chloro)dimethylsilane (1.06 g, 6.69 mmol, 1.1 eq) in DCM (10 mL) was added dropwise to a stirred soln, of 5- ((3-bromo-6-methylpyridin-2-yl)oxy)pentan-1 -ol (1.67 g, 6.08 mmol, 1 eq) and imidazol (832 mg, 12.20 mmol, 2 eq) in DCM (30 mL) at 0°C under N2 atmoshpere. The reaction was warmed to rt and stirred for 2h. The mixture was diluted with DCM and washed with brine. The org. layer was dried over MgSO4, filtered, and the solvent removedunder reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): IR= 1.31 min; [M+H]+: 388.0.3-(Benzylthio)-2-((5-((tert-butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine: A soln, of 3-bromo-2-((5- ((tert-butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine (815 mg, 2.10 mmol, 1 eq) in THF (15 mL) was cooled to -78°C. n-BuLi 1.6M in hexanes (1.6 mL, 2.52 mmol, 1.2 eq) was added dropwise while maintaining a temperature below -75°C. After 10 min, a soln, of benzyl disulfide (55 mg, 2.20 mmol, 1.05 eq) in THF (5 mL) was added dropwise at -78°C. The reaction mixture was stirred at -75°C for 1 h, quenched with ,H2O and extracted with DCM. The org. layer was washed with H2O, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.34 min; [M+H]+:432.1.2-((5-((fert-Butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine-3-sulfonyl chloride: At 0°C, AcOH (0.5 mL, 8.86 mmol, 2 eq) and H2O (0.16 mL, 8.86 mmol, 2 eq) were added to a stirred soln, of 3-(benzylthio)-2-((5-((fert- butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine (1.81 g, 4.43 mmol, 1 eq) in THF (25 mL). A soln, of 1,3- dichloro-5,5-dimethylhydantoin (2.62 g, 13.30 mmol, 3 eq) in THF (2 mL) was added dropwise. The reaction mixture was further stirred at 0°C for 15 min and then warmed to rt. After 10 min at , the reaction was diluted with DCM and washed with aq. sat. NaHCO3 soln. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): IR= 1.29 min; [M+H]+: 408.2. tert-Butyl ((2-((5-((fert-butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: At O°C, a sol. of 2-((5-((tert-butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridine-3-sulfonyl chloride (613 mg, 1.50 mmol, 1 eq) in DCM (5 mL) was added dropwise to a stirred soln, of L-proline f-butyl ester (0.26 mL, 1 .50 mmol, 1 eq) and DIPEA (1 .3 mL, 7.51 mmol, 5.0 eq) in DCM (5 mL). The reaction mixture was slowly warmed to rt and stirred for 15 min. The reaction was diluted with DCM and extracted with aq. sat. NaHCO3 soln. The org. layer was dried over .MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.30 min; [M+H]+: 543.3. tert-Butyl ((2-((5-hydroxypentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: At rt and under N2 atm, TBAF 1 M soln, in THF (1.3 mL, 4.49 mmol, 8.5 eq) was added to a stirred soln, of tert-butyl ((2-((5-((fert- butyldimethylsilyl)oxy)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (288 mg, 0.53 mmol, 1 eq) in THF (8 mL) and the reaction mixture was stirred at rt for 1h. The reaction was diluted with DCM and washed with a aq. sat. NaHCO3 soln. The org. layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 0.97 min; [M+H]+:429.1. tert-Butyl ((6-methyl-2-((5-oxopentyl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate: To a soln, of oxalyl chloride (47 μL, 0.54 mmol, 1 .5 eq) in DCM (1.5 mL) at -78°C was added a soln, of DMSO (68 pi L, 0.96 mmol, 2.7 eq) in DCM (1.5 mL) dropwise while maintaining a temperature below -70°C. After stirring for another 10 min, a soln, of tert-butyl ((2-((5-hydroxypentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (153 mg, 0.36 mmol, 1 eq) in DCM (3 mL) was added dropwise by keeping the temperature below -75°C. After stirring for another 10 min., TEA (0.25 mL, 1.79 mmol, 5 eq) was added and the soln, was stirred at -78°C for 30 min. The soln, was warmed to rt and stirred for 1 h. The reaction was diluted with DCM and washed with aq. sat. NaHCO3soln. The org. layer was dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.02 min; [M+H]+: 427.1. tert-Butyl ((2-((5-((4,4-difluorocyclohexyl)amino)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: To a soln, of tert-butyl ((6-methyl-2-((5-oxopentyl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate (671 mg, 1.57 mmol, 1 eq) in MeOH (16 mL) were added successively 4,4-difluorocyclohexan-1-amine (263 mg, 1.89 mmol, 1.2 eq) and NaBH(OAc)3(500 mg, 2.36 mmol, 1.5 eq). The resulting mixture was allowed to stir at rt overnight. The mixture was poured onto aq. sat. NaHCO3soln, and extracted with DCM. The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): IR= 0.87 min; [M+H]+: 546.4.((2-((5-((4,4-Difluorocyclohexyl)amino)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline: To a soln, of tert- butyl ((2-((5-((4,4-difluorocyclohexyl)amino)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (810 mg, 1.48 mmol, 1 eq) in DCM (10 mL) was added TFA (1.0 mL, 13.10 mmol, 8.8 eq) dropwise at 0°C. The mixture was allowed to stir at 0°C for 10 min and then was allowed to warm up to rt. The solvent was removed under reduced pressure. The residue was dissolved in toluene and removed under reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): IR= 0.71 min; [M+H]+: 490.3.(S)-11-(4,4-Difluorocyclohexyl)-3-methyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-pyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: ((2-((5-((4,4- difluorocyclohexyl)amino)pentyl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline (43 mg, 0.09 mmol, 1 eq) was dissolved in DMF (4 mL). DIPEA (0.12 mL, 0.70 mmol, 8 eq) and HATU (40 mg, 0.11 mmol, 1.2 eq) were added at rt and the mixture was stirred for 15 min. The soln, was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.02 min; [M+H]+: 472.0.Example 1.23 to Example 1.25 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)oxy)phenyl)sulfonyl)-L-prolinate in analogy to Example 1.14. LC-MS data of Example 1 .23 to Example 1 .25 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.26 (13R,42S)-6-(4,4-Difluorocyclohexyl)-26-methyl-3-thia-6-aza-2(2,3)-pyridina-1(1,3)-piperidina- 4(1,2)-pyrrolidinacyclooctaphan-5-one 3,3-dioxide: fert-Butyl (R)-3-(2-((4,4-difluorocyclohexyl)amino)ethyl)piperidine-1-carboxylate: Was synthesized using 4,4- difluorocyclohexan-1 -amine and tert-butyl (3R)-3-(2-oxoethyl)piperidine-1 -carboxylate in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 0.74 min; [M+H]+: 347.4. tert- Butyl (R)-3-(2-(((benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidine-1-carboxylate:Benzyl chloroformate (0.32 mL, 2.22 mmol, 1.1 eq) was added to a soln, of tert-butyl (R)-3-(2-((4,4- difluorocyclohexyl)amino)ethyl)piperidine-1 -carboxylate (700 mg, 2.02 mmol, 1 eq) and DI PEA (0.42 mL, 2.42 mmol, 1 .2 eq) in DCM (13 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was diluted with aq. sat. NaHCO3 soln, and DCM. The layers were separated, the org. layer was washed with H2O, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 50% EtOAc) to give the title compound. LC-MS (1): IR= 1.18 min; [M+H]+: 481.2.Benzyl (R)-(4,4-difluorocyclohexyl)(2-(piperidin-3-yl)ethyl)carbamate hydrochloride: 4M HCI soln, in dioxane (5.0 mL, 20.10 mmol, 10 eq) was added to a soln, of tert-butyl (R)-3-(2-(((benzyloxy)carbonyl)(4,4- difluorocyclohexyl)amino)ethyl)piperidine-1-carboxylate (968 mg, 2.01 mmol, 1 eq) in DCM (10 mL), and the reaction mixture was stirred at rt for 1 h. The solvent was removedunder reduced pressure. The crude product was used without further purification in the next step. LC-MS (1): IR= 0.77 min; [M+H]+: 381 .2.((2-((R)-3-(2-(((Benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-6-methylpyridin-3- yl)sulfonyl)-L-proline: A mixture of ((2-chloro-6-methylpyridin-3-yl)sulfonyl)-L-proline (275 mg, 0.90 mmol, 1 eq), (R)-(4,4-difluorocyclohexyl)(2-(piperidin-3-yl)ethyl)carbamate hydrochloride (752 mg, 1.80 mmol, 2 eq), and TMP (1.5 mL, 9.02 mmol, 10 eq) in DMF (5 mL) was stirred at 90°C for 3 days. The mixture was allowed to cool to rt, and was diluted with aq. 1 M HCI soln, and EtOAc. The layers were separated, the org. layer was washed with H2O and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): IR= 1.12 min; [M+H]+: 649.4.Methyl ((2-((R)-3-(2-((4,4-difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: ((2-((R)-3-(2-(((Benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-6-methylpyridin- 3-yl)sulfonyl)-L-proline (480 mg, 0.74 mmol, 1 eq) was dissolved in MeOH (8 mL). Aq. cone. HCI (0.35 mL, 3.70 mmol, 5 eq) and Pd / C (10%, wet, 50 mg) were added. The mixture was evacuated and purged with N2, then with H2, and was stirred under a H2atm for 8 days. The mixture was filtered through Celite, and the solvent removed under reduced pressure. The residue was dissolved in EtOH (7.5 mL), AcOH (0.21 mL) and Pd / C (10%, wet, 100 mg) were added. The mixture was purged as previously, and stirred under a H2atm overnight. AcOH (0.21 mL, 3.70 mmol, 5 eq) was added again and the mixture was stirred overnight under a H2atm. The mixture was filtered through a Whatmann® filter, washed with EtOH and the solvent removed under reduced pressure. The residue was purified by FC (DCM (0.5% NHs) to 25% MeOH) to give the title compound. LC-MS (1): IR= 0.82 min; [M+H]+:529.3.((2-((R)-3-(2-((4,4-Difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-6-methylpyridin-3-yl)sulfonyl)-L-proline:Was synthesized using methyl ((2-((R)-3-(2-((4,4-difluorocyclohexyl)amino)ethyl)piperidin-1 -yl)-6-methylpyridin-3- yl)sulfonyl)-L-prolinate in analogy to Example 1.8 to give the title compound. LC-MS (1): IR= 0.75 min; [M+H]+:515.3.(13R,42S)-6-(4,4-Difluorocyclohexyl)-26-methyl-3-thia-6-aza-2(2,3)-pyridina-1(1,3)-piperidina-4(1,2)- pyrrolidinacyclooctaphan-5-one 3,3-dioxide: Was synthesized using ((2-((R)-3-(2-((4,4- difluorocyclohexyl)amino)ethyl)piperidin-1 -yl)-6-methylpyridin-3-yl)sulfonyl)-L-proline in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 1.04 min; [M+H]+: 497.2.Example 1.27 to Example 1.29 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((2-((5-hyd roxypenty l)oxy)-4-methy I phenyl)sulfony l)-L-prol i nate in analogy to Example 1 .7. LC-MS data of Example 1.27 to Example 1.29 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.30 (6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14, 15- octahydrobenzo[e]pyrrolo[1,2-h][1,4]dioxa[7]thia[8,11]diazacyclotridecin-12(9H)-one 17,17-dioxide andExample 1.31 (6R,12aS)-11-(4,4-difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14,15- octahydrobenzo[e]pyrrolo[1,2-h][1,4]dioxa[7]thia[8,11]diazacyclotridecin-12(9H)-one 17,17-dioxide:2-(2-((4,4-Difluorocyclohexyl)amino)ethoxy)ethan-1-ol: Was synthesized using 4,4-difluorocyclohexanone and 2-(2-aminoethoxy)ethan-1-ol in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 0.38 min; [M+H]+: 224.4. tert-Butyl (4,4-difluorocyclohexyl)(2-(2-hydroxyethoxy)ethyl)carbamate: Was synthesized using 2-(2-((4,4- difluorocyclohexyl)amino)ethoxy)ethan-1-ol in analogy to Example 1.2 to give the title compound. LC-MS (1): IR= 0.89 min; [M+H]+: 324.4. tert- Butyl (4,4-difluorocyclohexyl)(2-(2-oxoethoxy)ethyl)carbamate: Was synthesized using tert-butyl (4,4- difluorocyclohexyl)(2-(2-hydroxyethoxy)ethyl)carbamate in analogy to Example 1.7 to give the title compound. LC- MS (1): tR= 0.95 min; [M+H]+: 322.1. tert-Butyl (RS)-(4,4-difluorocyclohexyl)(2-(2-hydroxypropoxy)ethyl)carbamate: tert-Butyl (4,4- difluorocyclohexyl)(2-(2-oxoethoxy)ethyl)carbamate (110 mg, 0.34 mmol, 1 eq) was dissolved in THF (4 mL), and the soln, was cooled to -78°C. 3M MeMgBr soln, in Et20 (0.10 mL, 0.41 mmol, 1.2 eq) was added dropwise at - 78°C. After addition, the mixture was stirred overnight while being allowed to warm up to rt. 3M MeMgBr soln, in Et20 (0.07 mL, 0.21 mmol, 0.6 eq) was added at rt. After 7h, 3M MeMgBr soln, in Et20 ( 0.21 mmol, 0.6 eq) was added again. After 3 days, 3M MeMgBr soln, in Et20 (0.07 mL, 0.21 mmol 0.6 eq) were added. The reaction was quenched with aq. sat. NH4CI soln. DCM was added and the layers were separated. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 0.92 min; [M+H]+: 338.1. tert-Butyl ((2-(((RS)-1-(2-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)ethoxy)propan-2-yl)oxy)-4- methylphenyl)sulfonyl)-L-prolinate: Was synthesized using tert-butyl (RS)-(4,4-difluorocyclohexyl)(2-(2- hydroxypropoxy)ethyl)carbamate and tert-butyl ((2-hydroxy-4-methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 1.23 min; [M+H]+: 661.3.((2-(((RS)-1-(2-((4,4-Difluorocyclohexyl)amino)ethoxy)propan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline:Was synthesized using tert-butyl ((2-(((RS)-1-(2-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)ethoxy)propan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-prolinate in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 0.74 and 0.76 min; [M+H]+: 505.0.(6S,12aS)-11-(4,4-difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14,15-octahydrobenzo[e]pyrrolo[1,2- h][1,4]dioxa[7]thia[8,11]diazacyclotridecin-12(9H)-one 17,17-dioxide and (6R,12aS)-11-(4,4- difluorocyclohexyl)-3,6-dimethyl-6,7,10,11,12a,13,14,15-octahydrobenzo[e]pyrrolo[1,2- h][1,4]dioxa[7]thia[8,11]diazacyclotridecin-12(9H)-one 17,17-dioxide: Were synthesized using ((2-(((RS)-1-(2- ((4,4-difluorocyclohexyl)amino)ethoxy)propan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline in analogy to Example 1.1. The stereoisomers were separated by basic prep. HPLC to give (6S,12aS)-11-(4,4-difluorocyclohexyl)-3,6-di methyl-6, 7, 10, 11 , 12a, 13, 14, 15-octahydrobenzo[e]pyrrolo[1 , 2-h][ 1 ,4]dioxa[7]thia[8, 11 ]d i azacyclotrideci n- 12(9H)- one 17, 17-dioxide and (6R, 12aS)-11 -(4, 4-dif I uorocyclohexy l)-3, 6-di methyl-6, 7, 10,11,12a,13,14,15- octahydrobenzo[e]pyrrolo[1 ,2-h][1 ,4]dioxa[7]thia[8,11 ]diazacyclotridecin-12(9H)-one 17,17-dioxide. The absolute configuration at the methyl-center was attributed arbitrarily. First eluting diastereomer: LC-MS (1): tR= 1.00 min; [M+H]+: 487.3. Second eluting diastereomer: LC-MS (1): tR= 1.00 min; [M+H]+: 487.3.Example 1.32 (6R,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:(RS)-3-Bromo-2-((5-((fert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine: Was synthesized using (RS)-5-((tert-Butyldimethylsilyl)oxy)pentan-2-ol and 3-bromo-6-methlpyridin-2-ol in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.31 min; [M+H]+: 387.8.(RS)-3-(Benzylthio)-2-((5-((fert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine: Was synthesized using (RS)-3-bromo-2-((5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.35 min; [M+H]+: 432.1.(RS)-2-((5-((fert-Butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine-3-sulfonyl chloride: Was synthesized using (RS)-3-(benzylthio)-2-((5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.30 min; [M+H]+: 408.0. tert-Butyl ((2-(((RS)-5-((fert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: Was synthesized using (RS)-2-((5-((tert-butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridine-3- sulfonyl chloride and L-proline tert-butyl ester in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.32 min; [M+H]+: 543.1. tert-Butyl ((2-(((R)-5-hydroxypentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate and tert-butyl ((2- (((S)-5-hydroxypentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: At rt and under N2 atm, 1 M TBAF soln, in THF (3.8 mL, 3.83 mmol, 4 eq) was added to a stirred soln, of tert-butyl ((2-(((RS)-5-((tert- butyldimethylsilyl)oxy)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (520 mg, 0.96 mmol, 1 eq) in THF (10 mL) and the reaction mixture was stirred at rt for 1 h. The reaction was diluted with EtOAc and washed with aq. sat. NaHCO3 soln. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 50% EtOAc) to give tert-butyl ((2-(((S)-5-hydroxypentan-2-yl)oxy)-6- methylpyridin-3-yl)sulfonyl)-L-prolinate (first eluting diastereomer) and tert-butyl ((2-(((R)-5-hydroxypentan-2- yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (second eluting diastereomer). First eluting diastereomer: LC-MS (1): tR= 0.99 min; [M+H]+: 429.1. Second eluting diastereomer: LC-MS (1): tR= 0.98 min; [M+H]+: 429.1. tert-Butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate: Was synthesized using tert-butyl ((2-(((R)-5-hydroxypentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.04 min; [M+H]+: 427.1.tert-Butyl ((2-(((R)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: Was synthesized using tert-butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L- prolinate and 4,4-difluorocyclohexan-1-amine in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 0.89 min; [M+H]+: 546.4.((2-(((R)-5-((4,4-Difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline: Was synthesized using tert-butyl ((2-(((R)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3- yl)sulfonyl)-L-prolinate in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 0.73 min; [M+H]+: 490.0.(6R,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydropyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using ((2- (((R)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.03 min; [M+H]+: 472.0.Example 1.33. (6S,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: tert-Butyl ((6-methyl-2-(((S)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate: Was synthesized using fert-butyl ((2-(((S)-5-hydroxypentan-2-yl)oxy)-6-methylpy ridi n-3-yl)sulfony l)-L-prol i nate in analogy to Example 1 .22 to give the title compound. LC-MS (1): tR= 1.05 min; [M+H]+: 427.3. tert- Butyl ((2-(((S)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: Was synthesized using fert-butyl ((6-methyl-2-(((S)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L- prolinate and 4,4-difluorocyclohexan-1-amine in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 0.90 min; [M+H]+: 546.4.((2-(((S)-5-((4,4-Difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline: Was synthesized using fert-butyl ((2-(((S)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3- yl)sulfonyl)-L-prolinate in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 0.73 min; [M+H]+: 490.0.(6S,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydropyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using ((2- (((S)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.05 min; [M+H]+: 472.0.Example 1.34 (6R,11aS)-3,6-Dimethyl-10-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-7,8,9,10,11a,12,13,14-octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: tert-Butyl ((4-methyl-2-(((RS)-5-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)pentan-2- yl)oxy)phenyl)sulfonyl)-L-prolinate: Was synthesized using fert-butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)oxy)phenyl)sulfonyl)-L-prolinate and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1 -amine hydrochloride in analogy to Example 1.14 to give the title compound. LC-MS (1): IR= 0.93 and 0.94 min; [M+H]+: 561.4.((4-Methyl-2-(((RS)-5-((3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)amino)pentan-2-yl)oxy)phenyl)sulfonyl)-L-proline: Was synthesized using tert-butyl ((4-methyl-2-(((RS)-5-((3-(trifluoromethyl)bicyclo[1.1 .1]pentan-1- yl)amino)pentan-2-yl)oxy)phenyl)sulfonyl)-L-prolinate in analogy to Example 1.14 to give the title compound. LC- MS (1): tR= 0.77 and 0.79 min; [M+H]+: 505.0.(6R,11aS)-3,6-Dimethyl-10-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-7,8,9,10,11a,12,13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide and(6S,11aS)-3,6-Dimethyl-10-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-7,8,9,10,11a,12, 13,14- octahydrobenzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Were synthesized using (6 RS , 11 aS)-3, 6-di methyl- 10-(3-(trifl uoromethyl) bicyclo[ 1.1.1 ]pentan- 1 -y I)-7,8,9, 10, 11 a, 12, 13, 14-octahydrobenzo[b]pyrrolo[1 , 2-e]

[0001] oxa[4]th i a[5, 8]d iazacyclododeci n- 11 (6H)-one 16,16- dioxide in analogy to Example 1.14. The crude was purified basic prep. HPLC to give (6R, 11 aS)-3,6-dimethyl-10- (3-(trif luoromethyl) bicyclo[ 1 .1.1 ]pentan- 1 -yl)-7,8,9, 10, 11 a, 12, 13, 14-octahydrobenzo[b]pyrrolo[1 ,2- e]

[0001] oxa[4]thia[5,8]diazacyclododecin-11 (6H)-one 16, 16-dioxide (first eluting diastereomer) and (6S, 11 aS)-3,6- Di methyl- 10-(3-(trif I uoromethy l)bicyclo[ 1 .1.1 ]pentan-1 -y l)-7, 8,9, 10, 11 a, 12, 13, 14-octahydrobenzo[b]pyrrolo[1,2- e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide (second eluting diastereomer). First eluting diastereomer: LC-MS (1): tR= 1.08 min; [M+H]+: 487.3. Second eluting diastereomer: LC-MS (1): tR= 1.09 min; [M+H]+: 487.3.Example 1.35 to Example 1.38 were synthesized using the appropriate amine or amine salt derivative, tert-butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate or fert-Butyl ((6-methyl-2-(((S)-5- oxopentan-2-y l)oxy) pyrid i n-3-yl)sulfony l)-L-proli n ate in analogy to Example 1 .32. LC-MS data of Example 1 .35 to Example 1.38 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.39 (S)-3-Chloro-11-(4,4-difluorocyclohexyl)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H- benzo[b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: tert- Butyl ((2-bromo-4-chlorophenyl)sulfonyl)-L-prolinate: fert-Butyl L-prolinate (0.10 mL, 0.58 mmol, 1 eq), DMAP (7 mg, 0.06 mmol, 0.1 eq) and DIPEA (3.0 mL, 57.40 mmol, 98 eq) were dissolved in MeCN (3 mL). Then 2-bromo-4-chlorobenzenesulfonyl chloride (175 mg, 0.60 mmol, 1 eq) in MeCN (2 mL) was added. The reaction mixture was stirred at rt for 35 min. The solvent was removed under reduced pressure. The residue was purified by FC (Hept to 20% EtOAc) to give the title compound. LC-MS (1): IR= 1.09 min; [M+H]+: 425.9. tert-Butyl ((4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-L-prolinate: fert-Butyl ((2-bromo-4-chlorophenyl)sulfonyl)-L-prolinate (208 mg, 0.49 mmol, 1 eq), PdCl2(MeCN)2 (5 mg, 0.04 mmol, 0.04 eq) and SPhos (8 mg, 0.020 mmol, 0.04 eq) were added to a microwave vial. The vial was sealed, evacuated and backfilled with argon. Then dioxane (2 mL), TEA (0.15 mL, 1.07 mmol, 3 eq) and 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (0.08 mL, 0.53 mmol, 1 .5 eq) were added. The reaction mixture was stirred at 100°C for 2.5h. The reaction mixture was filtered through a pad of celite and rinsed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by FC (Hept to 20% EtOAc) to give the title compound. LC-MS (1): IR= 1.16 min; [M+H]+: 472.0. fert-Butyl ((4-chloro-2-hydroxyphenyl)sulfonyl)-L-prolinate: fert-Butyl ((4-chloro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)sulfonyl)-L-prolinate (157 mg, 0.33 mmol, 1 eq) was dissolved in THF (1 mL). The soln, was cooled to 0°C. Aq. 1 M NaOH soln. (0.75 mL, 0.75 mmol, 2.25 eq) and aq. 30% (w / w) soln. (0.07 mL, 0.67 mmol, 2 eq) were added dropwise consecutively. The reaction mixture was stirred at 0°C for 30 min, then warmed to rt and further stirred for 2h. Then, H2O and DCM were added to the reaction mixture. The aq. layer was extracted with DCM. The combined org. layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): IR= 0.98 min; [M+H]+: 362.0. fert-Butyl ((2-((5-((fert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentyl)oxy)-4- chlorophenyl)sulfonyl)-L-prolinate: fert-Butyl ((4-chloro-2-hydroxyphenyl)sulfonyl)-L-prolinate (56 mg, 0.16 mmol, 1 eq) was dissolved in THF (2.5 mL). The soln, was cooled to 0°C. Then fert-butyl (4,4-difluorocyclohexyl)(5- hydroxypentyl)carbamate (65 mg, 0.20 mmol, 1.3 eq) and PPh3 (50 mg, 0.19 mmol, 1.2 eq) were added followed by DEAD (-40% in toluene, 0.11 mL, 0.23 mmol, 1.5 eq). After the addition, the mixture was allowed to warm up to rt and stirred for 2h. The reaction mixture was diluted with DCM and washed with aq. 1 M HCI soln, and aq. sat. NaHCO3 soln. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): IR= 1.26 min; [M+H]+: 665.0.((4-Chloro-2-((5-((4,4-difluorocyclohexyl)amino)pentyl)oxy)phenyl)sulfonyl)-L-proline: fert-Butyl ((2-((5- ((fert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)pentyl)oxy)-4-chlorophenyl)sulfonyl)-L-prolinate (33 mg, 0.05 mmol, 1 eq) was dissolved in DCM (1 mL). Then TFA (0.15 mL, 1.97 mmol, 40 eq) was added. The reaction mixture was stirred at rt for 1h. The solvent was removed under reduced pressure to give the title compound. The crude product was used in the next step without further purification. LC-MS (1): tR= 0.76 min; [M+H]+: 508.9.(S)-3-Chloro-11-(4,4-difluorocyclohexyl)-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-benzo[b]pyrrolo[1,2- e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: ((4-Chloro-2-((5-((4,4- difluorocyclohexyl)amino)pentyl)oxy)phenyl)sulfonyl)-L-proline (46 mg, 0.09 mmol, 1 eq) was dissolved in DMF (1 mL). Then DIPEA (0.12 mL, 0.72 mmol, 8 eq) and HATU (41 mg, 0.11 mmol, 1.2 eq) were added. The reaction mixture was stirred at rt for 20 min. The residue was purified by basic prep. HPLC to give the title compound. LC- MS (1): tR= 1.05 min; [M+H]+: 490.9.Example 1.40 (6R,11aS)-10-((3R,6s)-1 ,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:Benzyl ((3s,6s)-1,1-difluorospiro[2.5]octan-6-yl)carbamate and benzyl ((3r,6r)-1,1-difluorospiro[2.5]octan-6- yl)carbamate: At O°C and under a N2 atm, 1 , 1-difluorospiro[2.5]octan-6-amine hydrochloride (5.0 g g, 24.00 mmol, 1 eq) was dissolved in MeCN (120 mL). DIPEA (9.0 mL, 52.80 mmol, 2.22 eq) was added. Benzyl chloroformate (4.3 mL, 28.80 mmol, 1.2 eq) was added dropwise and the reaction was stirred at 0°C for 30 min. The soln, was partially evaporated under reduced pressure and the residue was diluted with Et20 and washed with aq. 1 M HCI soln., aq. sat. NaHCCL soln. The org. layer was separated, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The crude was purified by recrystallization from Hept / toluene. The diastereomeric mixture was purified by chiral SFC (SFC 8 method) to give benzyl ((3s,6s)-1 , 1-difluorospiro[2.5]octan-6-yl)carbamate (first eluting diastereomer) and benzyl ((3r,6r)-1 , 1 -difluorospiro[2.5]octan-6-yl)carbamate (second eluting diastereomer). First eluting diastereomer: LC-MS (1): tR= 1.01 min; [M+H]+: 296.2. Second eluting diastereomer. LC-MS (1): tR= 1.00 min; [M+H]+: 296.2.(3s,6s)-1,1-Difluorospiro[2.5]octan-6-amine hydrochloride: Benzyl ((3s,6s)-1,1-difluorospiro[2.5]octan-6- yl)carbamate (1.15 g, 3.89 mmol, 1 eq) was dissolved in MeOH (40 mL) and the flask was flushed with argon. Pd / C (10%, -50% H2O, 207 mg, 0.097 mmol, 0.025 eq) was added and the reaction was stirred at rt under a H2 atm for 30 min. The reaction mixture was filtered through a 0.45 μm PTFE filter and washed with MeOH. Aq. 1.25M HCI soln, in MeOH (62.0 mL, 77.90 mmol, 20 eq) was added and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 0.43 min; [M+H]+: not seen.1H NMR (500 MHz, DMSO) δ: 7.80-8.27 (m), 3.01- 3.20 (m, 1 H), 1.94-2.05 (m, 2 H), 1 .66-1 .81 (m, 2 H), 1 .52-1 .59 (m, 2 H), 1 .30-1 .40 (m, 2 H), 1.26 (t, J = 8.6 Hz, 2 H).(6R,11aS)-10-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide: Was synthesized using tert-butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate and (3s, 6s)-1,1-difluorospiro[2.5]octan-6-amine hydrochloride in analogy to Example 1.32 to give the title compound. LC-MS (1): tR= 1.09 min; [M+H]+: 498.2.Example 1.41 (6R,11aS)-10-((3R,5s)-1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:Benzyl ((3s,5s)-1,1-difluorospiro[2.3]hexan-5-yl)carbamate and benzyl ((3r,6r)-1,1-difluorospiro[2.5]octan- 6-yl)carbamate: 1,1-Difluorospiro[2.3]hexan-5-amine hydrochloride (3.00 g, 16.80 mmol, 1 eq) was dissolved in MeCN (50 mL). Then, DIPEA (6.3 mL, 36.90 mmol, 2.2 eq) was added and the reaction mixture was cooled to 0°C. Benzyl chloroformate (3.0 mL, 20.20 mmol, 1.2 eq) was added dropwise and the reaction was stirred at 0°C for 2h. The soln, was partially evaporated under reduced pressure and the residue was diluted with Et20 and washed with aq. 1 M HCI soln., aq. sat. NaHCO3 soln, and H2O. The org. layer was separated, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The crude was purified by recrystallization from Hept / toluene. The diastereomeric mixture was purified by chiral SFC (SFC 9 method) to give benzyl ((3s,5s)-1 ,1- difluorospiro[2.3]hexan-5-yl)carbamate (first eluting diastereomer) and benzyl ((3r,5r)-1 ,1-difluorospiro[2.3]hexan- 5-yl)carbamate (second eluting diastereomer). First eluting diastereomer: LC-MS (1): tR= 0.96 min; [M+H]+: 309.. Second eluting diastereomer: LC-MS (1): tR= 0.95 min; [M+H]+: 309.1.(3s,5s)-1,1-Difluorospiro[2.3]hexan-5-amine hydrochloride: Benzyl ((3s,5s)-1 , 1-difluorospiro[2.3]hexan-5- yl)carbamate (1.34 g, 5.01 mmol, 1.0 eq) was dissolved in MeOH (50 mL) and the flask was flushed with argon. Pd / C (10%, -50% H2O, 267 mg, 0.13 mmol, 0.025 eq) was added and the reaction was stirred at rt under a H2 atm for 30 min. The reaction mixture was filtered through a 0.45 μm PTFE filter and washed with MeOH. 1 .25 M HCI soln, in MeOH (75.0 mL, 100.00 mmol, 20 eq) was added and the solvent removed under reduced pressure to give the title compound.1H NMR (500 MHz, MeOD) δ: 4.05 (quint, J = 7.5 Hz, 1 H), 2.52-2.54 (m, 4 H), 1 .44 (t, J = 8.6 Hz, 2 H).(6R,11aS)-10-((3R,5s)-1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide: Was synthesized using tert-butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate and (3s, 5s)- 1 , 1 -difluorospiro[2.3]hexan-5-amine hydrochloride in analogy to Example 1.22 to give the title compound. LC-MS (1): tR= 1.03 min; [M+H]+: 487.0.Example 1.42 to Example 1.43 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methy l-2-(((S)-5-oxopentan-2-yl )oxy)py rid i n-3-yl)su lfonyl)-L-prol i n ate in analogy to Example 1 .32. LC-MS data of Example 1 .42 to Example 1 .43 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.44 (6R,11aS)-10-((3S,6r)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:(3r,6r)-1,1-Difluorospiro[2.5]octan-6-amine hydrochloride: Benzyl ((3r,6r)-1 ,1-difluorospiro[2.5]octan-6- yl)carbamate (Example 1.40) (50 mg, 0.17 mmol, 1 eq) was dissolved in MeOH (3 mL) and the flask was flushed with argon. Pd / C (10%, -50% H2O, 9.0 mg, 0.004 mmol, 0.025 eq) was added and the reaction was stirred at rt under a H2atm for 30 min. The reaction mixture was filtered through a 0.45 μm PTFE filter and washed with MeOH. 1.25M HCI soln, in MeOH (2.7 mL, 3.39 mmol, 20 eq) was added and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 0.45 min; [M+H]+: not seen.1H NMR (500 MHz, DMSO) 3: 7.94-8.25 (m, 3 H), 3.00-3.18 (m, 1 H), 1.88-2.04 (m, 2 H), 1.67-1 .72 (m, 2 H), 1 .33-1.57 (m, 4 H), 1.24 (t, J = 8.6 Hz, 2 H).(6R,11aS)-10-((3S,6r)-1,1-Difluorospiro[2.5]octan-6-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide: Was synthesized using (3r,6r)-1,1-difluorospiro[2.5]octan-6-amine hydrochloride and tert-butyl ((6-methyl-2-(((R)-5- oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1 .32 to give the title compound. LC-MS (1): tR= 1.09 min; [M+H]+: 498.0.Example 1.45 (6R,11aS)-10-((3S,5r)-1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide:(3r,5r)-1,1-Difluorospiro[2.3]hexan-5-amine hydrochloride: Benzyl ((3r,5r)-1,1-difluorospiro[2.3]hexan-5- yl)carbamate (Example 1.41) (1.75 g, 5.01 mmol, 1 eq) was dissolved in MeOH (50 mL) and the flask was flushed with argon. Pd / C (10%, -50% H2O, 348 mg, 0.13 mmol, 0.025 eq) was added and the reaction was stirred at rt under a H2atm for 30 min. The reaction mixture was filtered through a 0.45 μm PTFE filter and washed with MeOH. 1.25M HCI soln, in MeOH (105.0 mL, 131.00 mmol, 20 eq) was added and the solvent removed under reduced pressure to give the title compound. LC-MS (1): tR= 0.31 min; [M+H]+: 134.2.(6R,11aS)-10-((3S,5r)-1,1-Difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16,16-dioxide: Was synthesized using (3r,5r)-1 ,1-difluorospiro[2.3]hexan-5-amine hydrochloride and tert-butyl ((6-methyl-2-(((R)-5-oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate to Example 1.32 to give the title compound. LC-MS (1): tR= 1.04 min; [M+H]+: 470.0.Example 1.46 (6S,11aS)-10-((3S,5r)-1,1-difluorospiro[2.3]hexan-5-yl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydropyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclododecin-11(6H)-one 16, 16-dioxide: Was synthesized using (3r,5r)-1,1-difluorospiro[2.3]hexan-5-amine hydrochloride and tert-butyl ((6-methyl-2-(((S)-5- oxopentan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1 .32 to give the title compound. LC-MS (1): tR= 1.06 min; [M+H]+: 470.0.Example 1.48 to Example 1.50 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methyl-2-((5-oxopentyl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.22. LC-MS data of Example 1.48 to Example 1.50 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.51 (6R, 12aS)-11 -(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9, 10, 11 , 12a, 13, 14, 15-decahydro-12H-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide:(S)-6-((fert-Butyldimethylsilyl)oxy)hexan-2-ol: 0.5M 3-(tert-Butyldimethylsiloxy)propylmagnesium bromide soln, in THF (4.1 mL, 2.05 mmol, 1.2 eq) was added dropwise to a stirred suspension of Cui (33 mg, 0.17 mmol, 0.1 eq) in THF (1 mL) at 0°C under argon. After stirring for 5 min at 0°C, a soln, of (S)-(-)-propylene oxide (0.12 mL, 1.70 mmol, 1 eq) in THF (1 mL) was added dropwise. The mixture was allowed to warm up to rt and stirred for 1 ,5h. The mixture was poured onto aq. sat. NH4CI soln, and extracted with Et20. The org. layer was washed with H2O, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 1.06 min; [M+H]+: 233.2.(R)-3-Bromo-2-((6-((fert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine: DEAD (-40% in toluene, 0.50 mL, 1.02 mmol, 2 eq) was added dropwise to a stirred soln, of 3-bromo-6-methylpyridin-2-ol (100 mg, 0.51 mmol, 1 eq), (S)-6-((tert-butyldimethylsilyl)oxy)hexan-2-ol (198 mg, 0.51 mmol, 1 eq) and PPha (163 mg, 0.61 mmol, 1.2 eq) in THF (5 mL) at 0°C under argon. The mixture was stirred for 30 min at 0°C. The reaction was diluted withEt2O and washed with aq. 1 M HCI soln., aq. sat. NaHCO3 soln, and H2O. The org. layer was dried over Na2SO4 and evaporated. The residue was purified by FC (Hept to 50% EtOAc) to give the title compound. LC-MS (1): tR= 1.33 min; [M+H]+: 402.0.(R)-3-(Benzylthio)-2-((6-((tert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine: A soln, of (R)-3- bromo-2-((6-((tert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine (165 mg, 0.31 mmol, 1 eq) in THF (2 mL) was cooled to -78°C. 1 ,6M n-BuLi soln, in hexanes (0.23 mL, 0.37 mmol, 1.2 eq) was added while maintaining the temperature below -70°C. After 20 min, a soln, of benzyl disulfide (157 mg, 0.62 mmol, 2 eq) in THF (1 mL) was added dropwise at -70°C. The reaction was allowed to warm up to rt. The mixture was quenched with H2O and extracted with Et20. The org. layer was washed with H2O, dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 50% EtOAc) to give the title compound. LC-MS (1): tR= 1.36 min; [M+H]+: 446.4.(R)-2-((6-((fert-Butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine-3-sulfonyl chloride: At 0°C, AcOH (0.36 mL, 0.63 mmol, 2 eq) and H2O (0.11 mL, 0.63 mmol, 2 eq) were added to a stirred soln, of (R)-3-(benzylthio)- 2-((6-((tert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine (135 mg, 0.31 mmol, 1 eq) in THF (2 mL). Then a soln, of DCDMH (189 mg, 0.94 mmol, 3 eq) in THF (1 mL) was added dropwise. The reaction was diluted with DCM and washed with aq. sat. NaHCO3 soln, and H2O. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR= 1.33 min; [M+H]+: 422.2. tert-Butyl ((2-(((R)-6-((fert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: A soln, of (R)-2-((6-((tert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridine-3-sulfonyl chloride (213 mg, 0.30 mmol, 1 eq) in DCM (1 mL) was added dropwise to a soln, of tert-butyl L-prolinate (59 mg, 0.33 mmol, 1.1 eq) and DIPEA (0.26 mL, 1.51 mmol, 5 eq) in DCM (2 mL). The soln, was stirred at rt for 10 min. The soln, was then diluted with Et20 and washed with aq. 1 M HCI soln., aq. sat. NaHCO3 soln, and H2O. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): tR= 1.34 min; [M+H]+: 557.2. tert-Butyl ((2-(((R)-6-hydroxyhexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate: fert-Butyl ((2-(((R)-6- ((tert-butyldimethylsilyl)oxy)hexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (405 mg, 0.73 mmol, 1 eq) was dissolved in THF (8 mL). 1 M TBAF soln, in THF (2.9 mL, 2.91 mmol, 4 eq) was added dropwise at rt. The reaction was then allowed to stir at rt for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in Et20 and washed with H2O. The org. layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC- MS (1): tR= 1.01 min; [M+H]+: 443.1. tert-Butyl ((6-methyl-2-(((R)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate: A soln, of oxalyl chloride (0.10 mL, 1.17 mmol, 1.5 eq) in DCM (12 mL) was cooled to -78°C. DMSO (0.15 mL, 2.10 mmol, 2.7 eq) was added dropwise while maintaining the temperature below -70°C. After stirring for another 10 min, a soln, of tert-butyl ((2-(((R)-6-hydroxyhexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (344 mg, 0.78 mmol, 1 eq) in DCM (4 mL) was added dropwise, still keeping the temperature below -70°C. After 10 min stirring, TEA (1.0 mL, 7.42 mmol, 5 eq) was added and the soln, was stirred at -78°C for 30 min. Then the reaction mixture was allowed to warm up to it After 1 h, the mixture was diluted with Et2O and washed with aq. 1 M HCI soln., aq. sat. NaHCO3soln., and H2O. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.06 min; [M+H]+: 441.1. tert-Butyl ((2-(((R)-6-((4,4-difluorocyclohexyl)amino)hexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L- prolinate: A soln, of tert-butyl ((6-methyl-2-(((R)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate (15 mg, 0.034 mmol, 1 eq) and DIPEA (7 μL, 0.041 mmol, 1.2 eq) in MeOH (0.5 mL) was added to 4,4- difluorocyclohexylamine hydrochloride (6 mg, 0.034 mmol, 1 eq). NaBH(OAc)3(11 mg, 0.051 mmol, 1.5 eq) was added and the mixture was shaken at rt overnight. The mixture was quenched with aq. sat. NaHCO3soln, and diluted with DCM. The layers were separated through a phase separator. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure, to give the title compound. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.90 min; [M+H]+: 560.4.((2-(((R)-6-((4,4-Difluorocyclohexyl)amino)hexan-2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline: TFA (0.10 mL, 1.36 mmol, 40 eq) was added to a soln, of tert-butyl ((2-(((R)-6-((4,4-difluorocyclohexyl)amino)hexan-2- yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-prolinate (19 mg, 0.034 mmol, 1 eq) in DCM (0.5 mL). The mixture was shaken at rtfor 2h. The solventwas removed under reduced pressure to give the title compound. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.74 min; [M+H]+: 504.3.(6R,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro-12H-pyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: DIPEA (29 μL, 0.17 mmol, 5 eq) and HATU (17 mg, 0.044 mmol, 1.3 eq) were added to a soln, of ((2-(((R)-6-((4,4-difluorocyclohexyl)amino)hexan- 2-yl)oxy)-6-methylpyridin-3-yl)sulfonyl)-L-proline (17 mg, 0.034 mmol, 1 eq) in DMF (1 mL). The mixture was stirred at rt for 1h. Additional DIPEA (20 μL, 0.12 mmol, 3.5 eq) and HATU (9 mg, 0.024 mmol, 0.7 eq) were added until the reaction showed no further conversion. The title compound was isolated from the reaction mixture by basic prep. HPLC. LC-MS (1): tR=1.06 min; [M+H]+: 486.0.Example 1.52 to Example 1.54 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methyl-2-(((R)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.51. LC-MS data of Example 1 .52 to Example 1 .54 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.55 (6R,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[k]pyrrolo[1,2-b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide and Example 1.56 (6S,11aS)-10-(4,4-Difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14- octahydrobenzo[k]pyrrolo[1,2-b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide: tert-Butyl ((2-(((RS)-5-hydroxypentan-2-yl)thio)-4-methylphenyl)sulfonyl)-L-prolinate: A suspension of K2CO3 (144 mg, 1.04 mmol, 0.5 eq) in xylene (4 mL) was cooled to 0°C and 4-mercaptopentan-1-ol (250 mg, 2.08 mmol, 1 eq) was added dropwise. This mixture was stirred at rt for 1 ,5h. Another flask was charged with tert-butyl ((2- bromo-4-methylphenyl)sulfonyl)-L-prolinate (770 mg, 1.90 mmol, 0.9 eq), Pd2(dba)s (294 mg, 0.31 mmol, 0.15 eq), xantphos (217 mg, 0.37 mmol, 0.18 eq) and xylene (20 mL). This flask was evacuated and purged with N2, and stirred at rt for 20 min. This mixture was then added to the potassium thiolate soln, above, and the resulting mixture was heated to reflux for 3 days. The mixture was allowed to cool to rt, and was diluted with H2O and EtOAc. The org. layer was washed with H2O and brine, dried with MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 100% EtOAc) to give the title compound. LC-MS (1): IR= 1.01 min; [M+H]+: 444.3. tert-Butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)thio)phenyl)sulfonyl)-L-prolinate: Was synthesized using tert- butyl ((2-((( RS)-5-hydroxypentan-2-y l)thio)-4-methy I phenyl)sulfony l)-L-prol i nate in analogy to Example 1 .7 to give the title compound. LC-MS (1): IR= 1.06 min; [M+H]+: 442.3. tert-Butyl ((2-(((RS)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)thio)-4-methylphenyl)sulfonyl)-L- prolinate: Was synthesized using tert-butyl ((4-methyl-2-(((RS)-5-oxopentan-2-yl)thio)phenyl)sulfonyl)-L-prolinate and 4,4-difluorocyclohexan-1-amine in analogy to Example 1.1 to give the title compound. LC-MS (1): IR= 0.90; [M+H]+: 561.3.((2-(((RS)-5-((4,4-Difluorocyclohexyl)amino)pentan-2-yl)thio)-4-methylphenyl)sulfonyl)-L-proline: 4M HCI soln, in dioxane (1.1 mL, 4.46 mmol, 10 eq) was added to a soln, of tert-butyl ((2-(((RS)-5-((4,4- difluorocyclohexyl)amino)pentan-2-yl)thio)-4-methylphenyl)sulfonyl)-L-prolinate (250 mg, 0.45 mmol, 1 eq) in DCM(5 mL) at 0°C. The mixture was stirred overnight while warming up to rt. The solvent was removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.74; [M+H]+: 505.3.(6R,11aS)-10-(4,4-difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydrobenzo[k]pyrrolo[1,2- b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide and (6S,11aS)-10-(4,4-difluorocyclohexyl)- 3,6-dimethyl-7,8,9,10,11a,12,13,14-octahydrobenzo[k]pyrrolo[1,2-b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide: Were synthesized using ((2-(((RS)-5-((4,4-difluorocyclohexyl)amino)pentan-2-yl)thio)- 4-methylphenyl)sulfonyl)-L-proline in analogy to Example 1 .1 to give the title compounds. The stereosiomers were separated by acidic prep HPLC to give (6R,11aS)-10-(4,4-difluorocyclohexyl)-3,6-dimethyl-7,8,9,10,11a, 12,13,14- octahydrobenzo[k]pyrrolo[1 ,2-b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide (first eluting diastereomer) and (6S, 11 aS)-10-(4,4-difluorocydohexyl)-3,6-dimethyl-7,8,9, 10, 11 a, 12, 13, 14- octahydrobenzo[k]pyrrolo[1 ,2-b][1,10]dithia[2,5]diazacyclododecin-11(6H)-one 16,16-dioxide (second eluting diastereomer). First eluting diastereomer: LC-MS (1): IR= 1.04 min; [M+H]+: 487.3. Second eluting diastereomer: LC-MS (1): tR= 1 .07 min; [M+H]+: 487.3. The absolute stereochemistry at the methyl centerwas attributed arbitrarily.Example 1.57 to Example 1.58 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methyl-2-(((R)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.51, followed by prep, chiral SFC (SFC 5 method) to separate the stereoisomers. LC-MS data of Example 1.57 to Example 1 .58 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.59 (13R,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1(1,3),4(1,2)-dipyrrolidina-2(1,2)- benzenacyclooctaphan-5-one 3,3-dioxide and Example 1.60 (13S,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl- 3-thia-6-aza-1(1,3),4(1,2)-dipyrrolidina-2(1,2)-benzenacyclooctaphan-5-one 3,3-dioxide:Methyl ((2-fluoro-4-methylphenyl)sulfonyl)-L-prolinate: A soln, of methyl L-prolinate hydrochloride (2.09 g, 12.00 mmol, 1 eq), DIPEA (6.2 mL, 35.90 mmol, 3 eq), and DMAP (146 mg, 1.20 mmol, 0.1 eq) in DCM (50 mL) was cooled to 0°C. 2-Fluoro-4-methylbenzenesulphonyl chloride (2.50 g, 12.00 mmol, 1 eq) was added, and the clear light yellow soln, was stirred overnight while warming up to rt. Aq. sat. NaHCO3 soln, was added. The layers were separated, the org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent removed underreduced pressure. The residue was purified by FC (Hept to 75% EtOAc) to give the title compound. LC-MS (1): tR= 0.88; [M+H]+: 302.2.((2-Fluoro-4-methylphenyl)sulfonyl)-L-proline: Aq. 2M LiOH soln. (17.0 mL, 33.40 mmol, 3 eq) was added to a soln, of methyl ((2-fluoro-4-methylphenyl)sulfonyl)-L-prolinate (3.35 g, 11.10 mmol, 1 eq) in THF (45 mL). The mixture was stirred for 1 h, and the solvent was partially removed under reduced pressure. The residue was cooled to 0°C and acidified to pH 1 with aq. cone. HCI soln. (ca. 5 mL). The mixture was extracted with EtOAc. The org. layer was washed with H2O and brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR= 0.75; [M+H]+: 288.2. fert-Butyl-(RS)-3-(2-((4,4-difluorocyclohexyl)amino)ethyl)pyrrolidine-1-carboxylate: Was synthesized using tert-butyl-(RS)-3-(2-oxoethyl)pyrrolidine-1 -carboxylate and 4,4-difluorocyclohexan-1-amine in analogy to Example 1.1 to give the title compound. LC-MS (1): tR= 0.70; [M+H]+: 333.3. tert-Butyl-(RS)-3-(2-(((benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)pyrrolidine-1-carboxylate: Benzyl chloroformate (0.17 mL, 1.19 mmol, 1.1 eq) was added dropwise to a soln, of tert-butyl-(RS)-3-(2-((4,4- difluorocyclohexyl)amino)ethyl)pyrrolidine-1-carboxylate (360 mg, 1.08 mmol, 1 eq) and DIPEA (0.22 mL, 1.30 mmol, 1 .2 eq) in DCM (8 mL) at 0°C. The mixture was stirred for 1h at 0°C, and was diluted with aq. sat. NaHCOs soln, and DCM. The org. layer was separated through a phase separator and washed with H2O. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 50% EtOAc) to give the title compound. LC-MS (1): tR= 1.15; [M+H]+: 467.4.Benzyl-(RS)-(4,4-difluorocyclohexyl)(2-(pyrrolidin-3-yl)ethyl)carbamate hydrochloride: TFA (0.81 mL, 10.50 mmol, 10 eq) was added to a soln, of tert-butyl-(RS)-3-(2-(((benzyloxy)carbonyl)(4,4- difluorocyclohexyl)amino)ethyl)pyrrolidine-1-carboxylate (491 mg, 1.05 mmol, 1 eq) in DCM (10 mL) at 0 °C, and the mixture was stirred at 0°C for 1 ,5h. The mixture was quenched with aq.10% Na2CO3 soln, and extracted with DCM. The org. layer was washed with H2O, dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR= 0.75; [M+H]+: 367.4.((2-((RS)-3-(2-(((Benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)pyrrolidin-1-yl)-4- methylphenyl)sulfonyl)-L-proline: A microwave vial was charged with ((2-fluoro-4-methylphenyl)sulfonyl)-L- proline (125 mg, 0.44 mmol, 1 eq), benzyl-(RS)-(4,4-difluorocyclohexyl)(2-(pyrrolidin-3-yl)ethyl)carbamate hydrochloride (319 mg, 0.87 mmol, 2 eq), DIPEA (0.22 mL, 1.31 mmol, 3 eq) and DMSO (2 mL). The mixture was stirred at 110°C for 3 days. The mixture was allowed to cool to rt, and was diluted with H2O and EtOAc. The layers were separated and the org. layer was washed with H2O and brine. The org. layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.03; [M+H]+: 634.4.((2-((RS)-3-(2-((4,4-Difluorocyclohexyl)amino)ethyl)pyrrolidin-1-yl)-4-methylphenyl)sulfonyl)-L-proline: A suspension of ((2-((RS)-3-(2-(((benzyloxy)carbonyl)(4,4-difluorocyclohexyl)amino)ethyl)pyrrolidin-1 -yl)-4- methylphenyl)sulfonyl)-L-proline (170 mg, 0.27 mmol, 1 eq), Pd / C (10%, wet, 50 mg) and aq. cone. HCI soln. (0.13 mL, 1 .34 mmol, 5 eq) in EtOH (1 mL) was evacuated and purged with N2, then H2, and stirred under H2atm for 2h. The reaction mixture was diluted with EtOH, filtered through a 0.45 μm PTFE filter and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.70; [M+H]+: 500.0.(13R,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1(1,3),4(1,2)-dipyrrolidina-2(1,2)- benzenacyclooctaphan-5-one 3,3-dioxide and (13S,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl-3-thia-6-aza- 1(1,3),4(1,2)-dipyrrolidina-2(1,2)-benzenacyclooctaphan-5-one 3,3-dioxide: Were synthesized using ((2-((RS)- 3-(2-((4,4-difluorocyclohexyl)amino)ethyl)pyrrolidin-1 -yl)-4-methylphenyl)sulfonyl)-L-proline in analogy to Example 1.1. The mixture of diastereomers was separated by chiral SFC (SFC 2 method) to give (13R,42S)-6-(4,4- Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1 (1 ,3), 4(1 ,2)-dipyrrolidina-2(1 ,2)-benzenacydooctaphan-5-one 3,3- dioxide and (13S,42S)-6-(4,4-difluorocyclohexyl)-25-methyl-3-thia-6-aza-1 (1 ,3), 4(1 ,2)-dipyrrolidina-2(1,2)- benzenacyclooctaphan-5-one 3,3-dioxide. The stereochemistry at the pyrrolidine was attributed arbitrarily. First eluting diastereomer: LC-MS (1): IR= 1.03 min; [M+H]+: 482.3. Second eluting diastereomer: LC-MS (1): IR= 1.06 min; [M+H]+: 482.2.Example 1.61 (6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15-decahydro- 12H-pyrido[2,3-b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17,17-dioxide: Was synthesized using (R)-(+)-propylene oxide in analogy to Example 1.51 to give the title compound. LC-MS (1): tR=1.07 min; [M+H]+: 486.0.Example 1.62 (13R,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1(1,3)-piperidina-4(1,2)- pyrrolidina-2(1,2)-benzenacyclooctaphan-5-one 3,3-dioxide and Example 1.63 (13S,42S)-6-(4,4- Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1(1,3)-piperidina-4(1,2)-pyrrolidina-2(1,2)- benzenacyclooctaphan-5-one 3,3-dioxide:Benzyl (RS)-3-(2-((4,4-difluorocyclohexyl)amino)ethyl)piperidine-1 -carboxylate: Was synthesized using rac- benzyl (RS)-3-(2-oxoethyl)piperidine-1 -carboxylate and 4,4-difluorocyclohexan-1-amine in analogy to Example 1.1 to give the title compound. LC-MS (1): tp>=0.75; [M+H]+: 381.4.Benzyl (RS)-3-(2-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidine-1-carboxylate: Was synthesized using benzyl (RS)3-(2-((4,4-difluorocyclohexyl)amino)ethyl)piperidine-1 -carboxylate in analogy to Example 1.2 to give the title compound. LC-MS (1): tp=1.19; [M+H]+: 481.3. tert-Butyl (RS)-(4,4-difluorocyclohexyl)(2-(piperidin-3-yl)ethyl)carbamate: Pd / C (10%, wet, 160 mg) was added to a soln, of benzyl (RS)-3-(2-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidine-1- carboxylate (715 mg, 1.49 mmol, 1 eq) in EtOH (15 mL). The reaction mixture was evacuated and purged with N2, then with H2, and was stirred under a H2atm for 1h. The reaction mixture was purged with N2, and filtered over a0.45 μm PTFE filter. The filtrate was evaporated under reduced pressure. The residue was dissolved in DCM, filtered over Celite, and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR=0.74; [M+H]+: 347.3.((2-((RS)-3-(2-((tert-Butoxycarbonyl)(4,4-difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-4- methylphenyl)sulfonyl)-L-proline: A vial was charged with ((2-fluoro-4-methylphenyl)sulfonyl)-L-proline (220 mg, 0.77 mmol, 1 eq), tert-butyl ( RS)-(4, 4-d ifluorocyclohexy l)(2-(pi perid in-3-y l)ethyl)carbamate (531 mg, 1 .53 mmol, 2 eq), DIPEA (0.40 mL, 2.30 mmol, 3 eq) and DMSO (3 mL). The flask was sealed and the mixture was stirred at 110°C for 10 days. The mixture was allowed to cool to rt, and was diluted with H2O and EtOAc. The layers were separated, the org. layer was washed with H2O and brine, dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by acidic prep. HPLC to give the title compound. LC-MS (1): tR=1.1 1 ; [M+H]+: 614.4.((2-((RS)-3-(2-((4,4-Difluorocyclohexyl)amino)ethyl)piperidin-1-yl)-4-methylphenyl)sulfonyl)-L-proline: 4M HCI soln, in dioxane (0.55 mL, 2.18 mmol, 5 eq) was added to a soln, of ((2-((RS)-3-(2-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)ethyl)piperidin-1 -yl)-4-methylphenyl)sulfonyl)-L-proline (268 mg, 0.44 mmol, 1 eq) in DCM (2 mL). The mixture was stirred at rt for 2h. The solvents were removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR=0.77; [M+H]+: 514.2.(13R,42S)-6-(4,4-Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1(1,3)-piperidina-4(1,2)-pyrrolidina-2(1,2)- benzenacyclooctaphan-5-one 3,3-dioxide and (13S,42S)-6-(4,4-difluorocyclohexyl)-25-methyl-3-thia-6-aza- 1(1,3)-piperidina-4(1,2)-pyrrolidina-2(1,2)-benzenacyclooctaphan-5-one 3,3-dioxide: Was synthesized using ((2-(( RS)-3-(2-((4, 4-d ifl uorocydohexy I) am i no)ethy I) pi perid i n-1 -y l)-4-methy I ph enyl)sulfony l)-L-prol i ne in analogy to Example 1.1. The mixture of diastereomers was purified by acidic prep. HPLC to give (13R,42S)-6-(4,4- Difluorocyclohexyl)-25-methyl-3-thia-6-aza-1 (1 ,3)-piperidina-4(1 ,2)-pyrrolidina-2(1 ,2)-benzenacyclooctaphan-5- one 3,3-dioxide and (13S,42S)-6-(4,4-difl uorocydohexy l)-25-methyl-3-thia-6-aza-1 (1 , 3)-pi perid i n a-4( 1 ,2)- pyrrolidina-2(1 ,2)-benzenacyclooctaphan-5-one 3,3-dioxide. The stereochemistry at the piperidine center was attributed arbitrarily. First eluting diastereomer: LC-MS (1): tR= 0.84min; [M+H]+: 496.2. Second eluting diastereomer: LC-MS (1 ): tR= 1.08 min; [M+H]+: 496.3.Example 1.64 (6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,13,14,15,16- decahydrobenzo[b]pyrido[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12(12aH)-one 18, 18-dioxide:(R)-6-((fert-Butyldimethylsilyl)oxy)hexan-2-ol: Was synthesized using (3-((tert- buty Id i methy Isi ly l)oxy)propy l)m agnesi u m bromide and ( R)-(+)-propy lene oxide in analogy to Example 1 .61 to give the title compound. LC-MS (1 ): tR= 1.02 min; [M+H]+: 233.2.(S)-((5-(2-Bromo-5-methylphenoxy)hexyl)oxy)(fert-butyl)dimethylsilane: 2-Bromo-5-methylphenol (747 mg, 3.92 mmol, 1.3 eq) was dissolved in THF (47 mL). The soln, was cooled to 0°C. (R)-6-((fert- butyldimethylsilyl)oxy)hexan-2-ol (700 mg, 3.01 mmol, 1 eq) and PPha (962 mg, 3.61 mmol, 1.2 eq) were added followed by DEAD (-40% in toluene, 2.2 mL, 4.52 mmol, 1.5 eq). After the addition, the mixture was allowed towarm up to rt and stirred for 2h. The reaction mixture was diluted with DCM and washed with aq. 1 M HCI soln. The org. layer was treated with aq. 1 M NaOH soln, and the aq. layer was extracted with DCM. The org. layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 5% EtOAc) to give the title compound. LC-MS (1): IR= 1 .32 min; [M+H]+: 403.0.(S)-5-(2-Bromo-5-methylphenoxy)hexan-1-ol: (S)-((5-(2-Bromo-5-methylphenoxy)hexyl)oxy)(tert- butyl)dimethylsilane (678 mg, 1 .69 mmol, 1 eq) was dissolved in THF (17 mL). 1 M TBAF soln, in THF (2.0 mL, 2.03 mmol, 1.2 eq) was added and stirred at rt for 1 h. The reaction mixture was diluted with DCM. The org. layer was washed with H2O. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 45% EtOAc) to give the title compound. LC-MS (1): IR= 0.97 min; [M+H]+: 328.0.(S)-5-(2-Bromo-5-methylphenoxy)hexanal: Oxalyl chloride (0.16 mL, 1.83 mmol, 1.5 eq) was dissolved in DCM (20 mL) and the soln, was cooled to -78°C under argon atm. DMSO (0.23 mL, 3.29 mmol, 2.7 eq) was added dropwise while maintaining a temperature below -70°C. After stirring for another 10 min, a soln, of (S)-5-(2-bromo- 5-methylphenoxy)hexan-1-ol (350 mg, 1.22 mmol, 1 eq) in DCM (5 mL) was added dropwise. After stirring for another 10 min, TEA (0.85 mL, 6.09 mmol, 5 eq) was added and the reaction mixture was stirred at -78°C for 30 min. Then the soln, was allowed to warm up to rt. The reaction mixture was diluted with Et2O and washed with aq. 1 M HCI soln., aq. sat. NaHCO3 soln, and H2O. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 45% EtOAc) to give the title compound. LC-MS (1): tR= 1.02 min; [M+H]+: not seen.(S)-N-(5-(2-Bromo-5-methylphenoxy)hexyl)-4,4-difluorocyclohexan-1-amine: (S)-5-(2-Bromo-5- methylphenoxy)hexanal (625 mg, 2.19 mmol, 1 eq) was dissolved in MeOH (15 mL). Then 4,4- difluorocyclohexylamine hydrochloride (427 mg, 2.41 mmol, 1.1 eq) and DIPEA (0.75 mL, 4.38 mmol, 2 eq) were added and the soln, was stirred at rt overnight. NaBH4 (91 mg, 2.41 mmol, 1 .1 eq) was then added to the reaction mixture and stirring was continued for 10 min. The reaction mixture was diluted with EtOAc and washed with aq. sat. NaHCO3 soln. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure to give the title compound. The crude product was used in the next step without further purification. LC-MS (1): IR= 0.86 min; [M+H]+: 404.0. tert- Butyl (S)-(5-(2-bromo-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate: (S)-N-(5-(2-Bromo-5- methylphenoxy)hexyl)-4,4-difluorocyclohexan-1-amine (712 mg, 1.76 mmol, 1 eq) was dissolved in DCM (5 mL). TEA (0.52 mL, 3.70 mmol, 2.1 eq) and Boc2O (0.45 mL, 1.94 mmol, 1.1 eq) were added. The reaction mixture was stirred at rt for 20 min. The reaction mixture was diluted with DCM and washed with aq. 1 M HCI soln. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 45% EtOAc) to give the title compound. LC-MS (1): IR= 1 .26 min; [M+H]+: 503.9. tert-Butyl (S)-(5-(2-(benzylthio)-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate: tert-Butyl (S)-(5- (2-bromo-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate (455 mg, 0.90 mmol, 1 eq), Pd2(dba)s (83 mg,0.09 mmol, 0.1 eq) and XantPhos (108 mg, 0.18 mmol, 0.2 eq) were added in a vial. The vial was sealed, evacuated and purged with argon. Dioxane (7 mL), DIPEA (0.32 mL, 1.80 mmol, 2 eq) and benzyl mercaptan (0.13 mL, 1.08 mmol, 1.2 eq) were added. The reaction mixture was stirred at 100°C overnight. H2O was added and the reaction mixture was extracted with DCM. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was purified by FC (Hept to 15% EtOAc) to give the title compound. LC-MS (1): tR= 1.29 min; [M+H]+: 548.1. fert-Butyl (S)-(5-(2-(chlorosulfonyl)-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate: fert-Butyl (S)-(5-(2-(benzylthio)-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate (277 mg, 0.38 mmol, 1 eq) was dissolved in THF (12 mL). Then AcOH (44 μL, 0.77 mmol, 2 eq) and H2O (14 μL, 0.77 mmol, 2 eq) were added. The soln, was cooled to 0°C. DCDMH (232 mg, 1.15 mmol, 3 eq) was added in one portion. The reaction mixture was warmed to rt and stirred for 20 min. Aq. sat. NaHCO3 soln, was added and the reaction mixture was extracted with DCM. The org. layer was dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The crude product was used in the next step without further purification. LC-MS (1): tR= 1.24 min; [M+H]+: 524.0. fert-Butyl (S)-1-((2-(((S)-6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)hexan-2-yl)oxy)-4- methylphenyl)sulfonyl)piperidine-2-carboxylate: fert-Butyl (S)-piperidine-2-carboxylate (13 mg, 0.042 mmol, 1.1 eq), DMAP (0.5 mg, 0.004 mmol, 0.1 eq), and DIPEA (20 μL, 0.11 mmol, 3 eq) was dissolved in MeCN (0.5 mL). Then tert-butyl (S)-(5-(2-(chlorosulfonyl)-5-methylphenoxy)hexyl)(4,4-difluorocyclohexyl)carbamate (40 mg, 0.04 mmol, 1 eq) in MeCN (0.5 mL) was added. The reaction mixture was stirred at rt overnight. The crude product was purified by basic prep. HPLC to give the title compound. LC-MS (1): tR= 1.30 min; [M+H]+: 673.8.((2-(((S)-6-((4,4-Difluorocyclohexyl)amino)hexan-2-yl)oxy)-4-methylphenyl)sulfonyl)-L-proline: Was synthesized using tert-butyl (S)-1 -((2-(((S)-6-((fert-bu toxycarbony l)(4, 4-d if I uorocyclohexy l)ami no) hexan-2-yl)oxy)- 4-methylphenyl)sulfonyl)piperidine-2-carboxylate in analogy to Example 1.39 to give the title compound. LC-MS (1): tR= 0.80 min; [M+H]+: 517.0.(6S,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,13,14,15,16-decahydrobenzo[b]pyrido[1,2- e][1]oxa[4]thia[5,8]diazacyclotridecin-12(12aH)-one 18,18-dioxide: Was synthesized using ((2-(((S)-6-((4,4- difluorocyclohexyl)am i no)hexan-2-y l)oxy)-4-methy I pheny IJsulfony l)-L-proline in analogy to Example 1 .39 to give the title compound. LC-MS (1): tR= 1.12 min; [M+H]+: 499.0.Example 1.65 (6R,12aS)-11-(4,4-Difluorocyclohexyl)-3,6-dimethyl-6,7,8,9,10,11,13,14,15,16- decahydrobenzo[b]pyrido[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12(12aH)-one 18,18-dioxide: Was synthesized using (S)-6-((fert-butyldimethylsilyl)oxy)hexan-2-ol, 2-bromo-5-methylphenol, 4,4- difluorocyclohexylamine hydrochloride, and fert-Butyl (S)-pi perid i ne-2-carboxy I ate in analogy to Example 1 .64 to give the title compound. LC-MS (1): tR= 1.12 min; [M+H]+: 499.0.Example 1.66 (3R,10R)-5-(4,4-Difluorocyclohexyl)-2,3,10,13-tetramethyl-2,3,5,6,7,8,9,10-octahydro-4H- benzo[b][1]oxa[4]thia[5,8]diazacyclotridecin-4-one 1,1-dioxide: Was synthesized using tert-butyl methyl-D-alaninate hydrochloride in analogy to Example 1.65 to give the title compound. LC-MS (1): tR= 1.08 min; [M+H]+: 473.0.Example 1.67 to Example 1.72 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methyl-2-(((R)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.51. The diastereoisomers were separated by prep, chiral SFC (SFC 5 method). LC-MS data of Example 1.67 to Example 1.72 are listed in the table below. The LC-MS conditions used were LC-MS (1). The stereocenters of the amide substituent were arbitrarily defined.Example 1.73 to Example 1.74 were synthesized using the appropriate amine or amine salt derivative and tert- butyl ((6-methyl-2-(((S)-6-oxohexan-2-yl)oxy)pyridin-3-yl)sulfonyl)-L-prolinate in analogy to Example 1.61. LC-MS data of Example 1 .73 to Example 1 .74 are listed in the table below. The LC-MS conditions used were LC-MS (1).Example 1.75 (12S,51S,53R)-9-(4,4-Difluorocyclohexyl)-34-methyl-4-oxa-2-thia-9-aza-1(1,2)-pyrrolidina- 3(1 ,2)-benzena-5(1 ,3)-cyclobutanacyclodecaphan-10-one 2,2-dioxide:Ethyl (E)-3-((1r,3r)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)acrylate: A suspension of NaH (ca 60% in mineral oil, 67 mg, 1.68 mmol, 1.06 eq) in DME (6 mL) was cooled to 0°C. Triethylphosphonoacetate (0.34 mL, 1.68 mmol, 1.06 eq) was added at O°C, and the mixture was stirred for 10 min at 0°C, then for 30 min at it A soln, of (1 r,3r)-3- ((tert-butyldiphenylsilyl)oxy)cyclobutane-1 -carbaldehyde (WO2021124172) (535 mg, 1.58 mmol, 1 eq) in DME (1 mL) was added dropwise at it The mixture was stirred at rt for 1 h, and was diluted with Et20 and H2O. The aq. layer was extracted with Et20. The combined org. layers were dried over MgSCU, filtered, and the solvent removed under reduced pressure. The residue was purified by basic prep. HPLC to give the title co...

Claims

Claims1. A compound of Formula (I)wherein❖ Ring A is a 6-membered aromatic ring, wherein:> RA1represents hydrogen, (C1-3)alkyl, C1-3) alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl;> X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen, (C1-3)alkyl, or C1-3) alkoxy;> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen; and> X5represents C; and L represents:> linker group L1, wherein the backbone of said linker group L1is linear and consists of a total of 3 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 carbon atoms and 0 to 2 heteroatoms independently selected from 0, N or S; wherein said backbone is saturated or partially unsaturated; wherein said backbone is unsubstituted, or mono- , di- or tri-substituted; wherein the substituents are independently selected from the group consisting of:■ (Ci-e)alkyl;■ (C3-6)cycloalkan-1,1-diyl;■ (C3-6)cycloalkyl;■ hydroxy;■ halogen; and■ (C1-3)fluoroalkyl;> or linker group L2, wherein the backbone of said linker group L2consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 heteroatoms independently selected from 0, N or S; wherein said backbone is saturated or partially unsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6-membered saturated, partially unsaturated or aromatic cyclic moietycomprising a total of 0 to 3 heteroatoms independently selected from 0, N or S; wherein L2is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of:■ (C1-3)alkyl; and■ halogen;❖ or the fragment formed byFormula (l-B) wherein> Ring A represents a 6-membered aromatic ring, wherein:■ X2represents CH or N; and■ RA1represents independently hydrogen, (C1-3)alkyl, C1-3) alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C-i)fluoroalkyl; and Ring B represents a 5- to 7-membered heterocyclic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 or 2 ring heteroatoms; wherein said heteroatoms are independently selected from N, 0, or S;> Ring A represents a 6-membered aromatic ring, wherein:■ X2represents CH or N; and■ RA1represents independently hydrogen, (C1-3)alkyl, C1-3) alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C-i)fluoroalkyl; and Ring B represents a 5-membered heteroaromatic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 to 3 ring heteroatoms; wherein said heteroatoms are independently selected from N, 0, or S; or> Ring A represents a 6-membered aromatic ring, wherein:■ X2represents CH or N; and■ RA1represents independently hydrogen, (C1-3)alkyl, C1-3) alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (C-i)fluoroalkyl; and Ring B represents a 6-membered heteroaromatic ring; wherein said Ring B including ring atoms X1and X5contains a total of 1 or 2 ring heteroatoms; wherein said ring heteroatoms are N;and L3represents:> a linear linker group; wherein L3consists of a total of 3 or 4 backbone atoms; wherein said backbone atoms are independently selected from 3 or 4 carbon atoms and 0 or 1 heteroatom independently selected from 0, N or S; wherein said backbone is saturated or mono-unsaturated; wherein said backbone is unsubstituted or mono-substituted with (C1-3)alkyl; or halogen;X3represents SO2 or S(=O)(=NR3), wherein R3represents hydrogen, (C1-3)alkyl, monocyclic (C3.6)cycloalkyl, or phenyl;X4represents:> NRN1; wherein: o RN1represents hydrogen or (C1-3)alkyl; and o R1represents (C1-5)alkyl or - (CH2)n-(C3-4)cycloalkyl wherein n independently represents the integer 0 or 1 ;> NRN1; wherein R1and RN1together form a ring comprising X4, herein Ring E, wherein said Ring E represents: o a 4- to 6-membered saturated monocyclic heterocycloalkan-d iyl comprising X4and zero or one ring oxygen atom; wherein said heterocydoalkan-diyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl, halogen, C1-3) alkoxy, hydroxy, phenyl, and cyano; or o a 6- to 8-membered saturated spiro, fused, or bridged bicyclic heterocydoalkan-diyl comprising X4;> or CHRC1; wherein R1and RC1together form a ring comprising X4, herein Ring F, wherein said Ring F represents a monocyclic (Cs-ejcycloalkan-diyl or a monocyclic 5- or 6-membered heterocydoalkan-diyl comprising one ring oxygen atom; andR2represents:> 3-cyano-3,3-dimethylpropyl;> -(CH2)m-(Ring D), wherein m is the integer 0 or 1 , and Ring D represents: o a saturated monocyclic (C^cycloalkyl; wherein said (C^cycloalkyl is unsubstituted, mono-, di- , or tri-substituted; wherein the substituents are independently selected from the group consisting of:■ C1-3) alkyl; wherein said (C1-3)alkyl independently is unsubstituted or mono-substituted with cyano;■ halogen;■ (C1-3)fluoroalkyl;■ (C1-3)alkoxy;■ (C^cycloalkyl;■ carbamoyl;■ hydroxy;■ cyano; and■ (C2.3)alkynyl; o a saturated bicyclic ((C5-8)spirocycloalkyl; wherein said ((C5-8)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano, and hydroxy; o a saturated fused or bridged bicyclic ((C5-8)cycloalkyl; wherein said bicyclic ((C5-8)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)fluoroalkyl, halogen, cyano, and carbamoyl; o a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from 0, NRN2, S, or S02; wherein RN2represents (C1-3)alkyl or cyanomethyl; wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl, halogen, (C1-3)fluoroalkyl, and oxo; o a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom; or o a 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein:Ring A is a 6-membered aromatic ring, wherein:> RA1represents hydrogen, (C1-3)alkyl, C1-3) alkoxy, halogen, monocyclic (C3-4)cycloalkyl, or (Ci)fluoroalkyl;> X1represents independently N or CRA3, wherein RA3represents hydrogen, halogen, (C1-3)alkyl, or (C1-3)alkoxy;> X2represents independently N or CRA2, wherein RA2represents hydrogen or halogen; and> X5represents C; and L represents:> linker group L1, wherein the backbone of said linker group L1is linear and consists of a total of 3 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 6 carbon atoms and 0 to 2 heteroatoms independently selected from 0, N or S; wherein said backbone is saturated or partially unsaturated; wherein said backbone is unsubstituted, or mono-, di- or tri-substituted; wherein the substituents are independently selected from the group consisting of: (Ci-e)alkyl; (C3- 6)cycloalkan-1,1-diyl; (C3.6)cycloalkyl; hydroxy; halogen, and (C1-3)fluoroalkyl;> or linker group L2, wherein the backbone of said linker group L2consists of a total of 4 to 6 backbone atoms; wherein said backbone atoms are independently selected from 3 to 5 carbon atoms and 1 or 2 heteroatom independently selected from 0, N or S; wherein said backbone is saturated or partiallyunsaturated; wherein 2 or 3 adjacent atoms of said backbone atoms are contained in a 3- to 6- membered saturated, partially unsaturated or aromatic cyclic moiety comprising a total of 0 to 3 heteroatoms independently selected from 0, N or S; wherein L2is unsubstituted, or mono- or di- substituted; wherein the substituents are independently selected from (C1-3)alkyl or halogen; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 2, wherein❖ L represents linker group L1and the backbone of linker group L1is selected from the group consisting of: *-O-(CH2)2-, *-O-(CH2)3-, -(CH2)4-, *-S-(CH2)3- *-O-(CH2)4-, *-(CH2)-O-(CH2)3- *-(CH2)3-O-(CH2)-, -(CH2)5- , *-NH-(CH2)2-CH=CH-, *-NH-(CH2)4-, *-CH=CH-(CH2)3-, *-O-(CH2)2-CH=CH-, *-O-(CH2)2-O-(CH2)-, *-O- (CH2)S-, and *-O-(CH2)2-NH-(CH2)-, wherein the asterisks indicate the attachment point of linker group L1to Ring A; wherein said backbone is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (Ci.6)alkyl, (C3-6)cycloalkan-1,1-diyl, (C3. ejcycloalkyl, hydroxy, halogen, and (C1-3)fluoroalkyl; or❖ L represents linker group L2and the backbone of linker group L2is selected from the group consisting of:> *-O-(CH2)-(cyclic moiety)-, *-0-(cyclic moiety)-(CH2)-, *-0-(cyclic moiety)-CH=CH-, *-O-(cydic moiety)-(CH2)2-; wherein independently the cyclic moiety of such linker group L2represents: o (C3-6)cycloalkan-1,2-diyl; o phen-1 ,2-diyl; or o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in ortho position relative to one another; or> ‘-(cyclic moiety)-(CH2)-, ‘-(cyclic moiety)-(CH2)2-, ‘-(cyclic moiety)-CH=CH-, ‘-(cyclic moiety)-(CH2)3-, ‘-□-(cyclic moiety)-, *-0-(cyclic moiety)-(CH2)-, and *-O-(CH2)-(cydic moiety)-; wherein independently the cyclic moiety of such linker group L2represents: o (C3.6)cycloalkan-1 ,3-diyl; o 5- or 6-membered heterocycloalkan-diyl; wherein said heterocycloalkan-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another; o 5- or 6-membered heteroaryl-diyl; wherein said heteroaryl-diyl is linked to the rest of the molecule via two of its ring atoms that are in meta position relative to one another; wherein the asterisks indicate the attachment point of linker group L2to Ring A; wherein said L2is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl and halogen; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2, whereinL represents linker group L1; said linker group L1independently is:**-O-CH(CH3)-CH2-; **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-O-cyclopropan-1,1-diyl-CH2-CH2-; - CH2-CH2-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-CH=CH-CH2-CH2-CH2-; **-O- CH2-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)- CH2-CH2-CH2-; **-O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2- CH(CH3)-CH2-CH2-; **-O-CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2- CH2-; **-O-CH2-CH2-C(CH3)2-CH2-; **-O-CH2-CH2-cyclopropan-1,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2-CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2- CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O-CH(CH3)-CH2-O-CH2-; **-NH-CH2-CH2-CH2-CH2-; **-N(CH3)- CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH=CH-; **-NH-CH(CH3)-CH2-CH=CH-; **-NH-CH(CH3)-CH2- CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O-CH(CH3)-CH2-CH(CH3)- CH2-; **-O-CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)-CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2- CH2-CH2-; **-O-CH2-CH2-CH(CF3)-CH2-;**-O-CH2-CH2-N(2,2,2-trifluoroethyl)-CH2-; or **-O-CH2-CH2- CH=CH-;L represents linker group L2; said linker group L2independently is:**-(pyrrolidin-1*,3-diyl)-CH2-; **-(piperidin-1 * 3-diyl)-CH2-; **-O-CH2-(cyclopropan-1,2-diyl)-; **-O-CH2- (cyclobutan-1 ,2-diyl)-; **-O-(cyclopentan-1 ,2-diyl)-C H2-; **-O-(cyclohexan-1 ,2-diyl)-C H2-; **-O- (cyclohexan-1 ,3-diyl)-; **-O-(cyclohexan-1 ,3-diyl)-CH2-; **-(py rrolidin- 1 *, 3-d iy l)-C H2-CH2-; **-O- (cydopentan-1 ,2-diyl)-CH=CH-; **-O-(cydopentan-1,3-diyl)-CH2-; **-O-(cyclopentan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclobutan-1 ,3-diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1,3*-diyl)- CH2-CH2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1 , 2-d iy l)-C H2-C H2-; **-O-CH2-CH2- (cyclopropan-1 ,2-diyl)-; **-O-([1,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin- 2,6-diyl)-CH2-CH2-; **-([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **- O-(tetrahydrofuran-2,4*-diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1 ,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1 ,3-diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; or **-O-(cyclohexan-1,2-diyl)-CH2- CH2-; **-O-CH2-(cyclopropan-1 ,2-diyl)-CH2-;**-O-CH(CH3)-CH2-(cydopropan-1,2-diyl)-; **-(pyrazol-1,3*- diyl)-CH2-CH2-; or **-O-(cydopentan-1,2-diyl)-O-CH2-; wherein the double asterisks indicate the attachment point of the linker group L1, respectively L2to Ring A; and, where applicable, the single asterisks indicate the attachment point of (i) the linker oxygen atom which is attached to Ring A, or (ii) of Ring A, as the case may be; or a pharmaceutically acceptable salt thereof.

5. A compound according to any of claims 1 to 4, wherein X3represents SO2or S (=O)(=N R3), wherein R3represents hydrogen or (C1-3)alkyl; or a pharmaceutically acceptable salt thereof.

6. A compound according to any of claims 1 to 5, wherein X4represents CHRC1, and R1and RC1together form a ring comprising X4, herein Ring F, wherein Ring F represents a monocyclic (Cs-ejcycloalkan-diyl;or a pharmaceutically acceptable salt thereof.

7. A compound according to any of claims 1 to 5, wherein X4represents NRN1, and R1and RN1together form a ring comprising X4, herein Ring E; wherein said Ring E represents: o a 5- or 6-membered saturated monocyclic heterocydoalkan-diyl comprising X4and zero or one ring oxygen atom; wherein said heterocycloalkan-diyl is unsubstituted or mono-substituted; wherein the substituents are independently selected from the group consisting of: C1-3) alkyl, halogen, and (C1-3)alkoxy; or o a 6- or 7-membered saturated fused or bridged bicyclic heterocycloalkan-diyl comprising X4; or a pharmaceutically acceptable salt thereof.

8. A compound according to any of claims 1 to 7, wherein R2represents:> 3-cyano-3,3-dimethylpropyl;> -(CH2)m-(Ring D), wherein m is the integer 0 or 1 , and Ring D represents: o a saturated monocyclic (C^cycloalkyl; wherein said (C^cydoalkyl is mono-, di-, or tri- substituted; wherein the substituents are independently selected from the group consisting of:■ (C1-3)alkyl; wherein said (C1-3)alkyl is unsubstituted or mono-substituted with cyano;■ halogen;■ (C1-3)alkoxy;■ (C^cycloalkyl;■ hydroxy; and■ cyano; o a saturated bicyclic ((C5-8)spirocycloalkyl; wherein said ((C5-8)spirocycloalkyl is unsubstituted, or mono-, di-, tri- or tetra-substituted; wherein the substituents are independently selected from the group consisting of: halogen, cyano, and hydroxy; o a saturated fused or bridged bicyclic ((C5-8)cycloalkyl; wherein said bicyclic ((C5-8)cycloalkyl is unsubstituted, or mono- or di-substituted; wherein the substituents are independently selected from the group consisting of: C1-3) fluoroalkyl, halogen, and cyano; o a 5- or 6-membered saturated monocyclic heterocycle comprising one ring heteroatomic group selected from 0, NRN2, or SO2; wherein RN2represents (C1-3)alkyl; wherein said heterocycle is unsubstituted, or mono-, di-, tri-, or tetra-substituted; wherein the substituents are independently selected from the group consisting of: (C1-3)alkyl and oxo; o a 9-membered saturated spiro bicyclic heterocycle comprising one ring oxygen atom;or o a 7-membered saturated fused or bridged bicyclic heterocycle comprising one ring oxygen atom; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 which is a compound of Formula (IV)> RA1independently represents hydrogen, (C1-3)alkyl, C1-3) alkoxy, or halogen; and> RA3, if present, independently represents hydrogen, halogen, or C1-3) alkyl;L represents:• linker group L1wherein such linker group L1independently is:**-O-CH(CH3)-CH2-; **-O-CH2-CH2-CH2-; **-O-CH(CH3)-CH2-CH2-; **-O-cyclopropan-1,1-diyl-CH2-CH2-; -CH2- CH2-CH2-CH2-; **-S-CH(CH3)-CH2-CH2-; -CH2-CH2-CH2-CH2-CH2-; **-CH=CH-CH2-CH2-CH2-; **-O-CH2-CH2- CH2-CH2-; **-O-CH(CH3)-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-CH2-CH2-; **-O-CH(n-propyl)-CH2-CH2-CH2-; **- O-CH(isopropyl)-CH2-CH2-CH2-; **-O-CH(cyclopropyl)-CH2-CH2-CH2-; **-O-CH2-CH(CH3)-CH2-CH2-; **-O- CH2-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-CH(ethyl)-CH2-; **-O-CH2-CF2-CH2-CH2-; **-O-CH2-CH2-C(CH3)2- CH2-; **-O-CH2-CH2-cyclopropan-1,1-diyl-CH2-; **-O-CH2-CH2-C(hydroxy)(cyclopropyl)-CH2-; **-O-CH2-CH2- CH2-CH(CH3)-; **-O-CH(CH3)-CH2-CH=CH-; **-CH2-O-CH2-CH2-CH2-; **-CH2-CH2-CH2-O-CH2-; **-O- CH(CH3)-CH2-O-CH2-; **-NH-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2-CH2-CH2-; **-N(CH3)-CH2-CH2- CH=CH-; **-NH-CH(CH3)-CH2-CH2-CH2-; or **-O-CH2-CH2-CH2-CH2-CH2-; **-O-CH(ethyl)-CH2-O-CH2-; **-O- CH2-CF2-CH2-CH2-; **-O-CH(CH3)-CH2-CH(CH3)-CH2-; **-O-CH2-CH2-N(cyclopropyl)-CH2-; **-O-CH(CH3)-CH2-N(cyclopropyl)-CH2-; **-O-CH(CF3)-CH2-CH2- CH2-; **-O-CH2-CH2-CH(CF3)-CH2-; or **-O-CH2-CH2- N(2,2,2-trifluoroethyl)-CH2-; wherein the double asterisks indicate the attachment point of said linker group L1to Ring A; or• linker group L2; wherein such linker group L2independently is:**-(py rrol id i n-1 *,3-diy l)-C H2-; **-(pi peridi n-1 *,3-diyl)-C H2-; **-O-CH2-(cyclopropan-1 ,2-diyl)-; **-O-CH2- (cyclobutan-1 ,2-diyl)-; **-O-(cyclopentan-1 ,2-diyl)-CH2-; **-O-(cyclohexan-1 ,2-diyl)-CH2-; **-O-(cyclohexan- 1 ,3-diyl)-; **-O-(cyclohexan-1,3-diyl)-CH2-; **-(pyrrolidin-1 *,3-diyl)-CH2-CH2-; **-O-(cyclopentan-1,2-diyl)- CH=CH-; **-O-(cydopentan-1 ,3-diyl)-CH2-; **-O-(cyclopentan-1 ,2-diyl)-CH2-CH2-; **-O-CH2-(cyclobutan-1,3- diyl)-; **-O-(tetrahydrofuran-3,4-diyl)-CH2-CH2-; **-(4-chloro-pyrazol-1 , 3*-d iyl)-CH2-C H2-; **-O-(tetrahydrofuran-2,3*-diyl)-CH2-CH2-; **-O-(cyclobutan-1,2-diyl)-CH2-CH2-; **-O-CH2-CH2-(cyclopropan-1,2- diyl)-; **-O-([1,3,4]oxadiazol-2,5-diyl)-CH2-; **-O-(phen-1,2-diyl)-CH2-CH2-; **-(pyridin-2,6-diyl)-CH2-CH2-; **- ([1,2,4]oxadiazol-3*,5-diyl)-CH2-CH2-CH2-; **-O-(cyclobutan-1,3-diyl)-CH2-CH2-; **-O-(tetrahydrofuran-2,4*- diyl)-CH2-; **-O-(tetrahydropyran-2,4*-diyl)-CH2-; **-O-(piperidin-1 ,3*-diyl)-CH2-; **-O-CH2-(cyclopentan-1,3- diyl)-; **-O-(tetrahydropyran-3,5-diyl)-CH2-; **-O-(cyclohexan-1,2-diyl)-CH2-CH2-; **-O-CH2-(cyclopropan-1,2- diyl)-CH2-; **-O-CH(CH3)-CH2-(cyclopropan-1,2-diyl)-; **-(pyrazol-1,3*-diyl)-CH2-CH2-; or **-O-(cyclopentan- 1 ,2-diyl)-O-CH2-; wherein the double asterisks indicate the attachment point of linker group L2to Ring A; and, where applicable, the single asterisks indicate the attachment point of (i) the linker oxygen atom which is attached to Ring A, or (ii) of Ring A, as the case may be;X3represents SO2or S(=O)(=NR3), wherein R3represents hydrogen or methyl;X4represents N or CH; andR2represents:> cyclopentyl or cyclohexyl; wherein said cyclopentyl or cyclohexyl independently is mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-3)alkyl, halogen, and cyano; or> a saturated bicyclic (C6-8)spirocycloalkyl; wherein said (C6-8)spirocycloalkyl is unsubstituted, or di-substituted with fluoro; or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 , which is selected from the following compounds: (6R, 12aS, 15aR)-11 -(4, 4-D if luorocyclohexyl)-3, 6-d i methyl-6,7, 8, 9, 10, 11 , 13, 14, 15, 15a- decahydrocyclopenta[e]pyrido[2,3-b][1 ]oxa[4]thi a[8]azacyclotrideci n- 12(12aH)-one 16, 16-dioxide;(6R,12aS,17S)-11-((3R,6s)-1,1-Difluorospiro[2.5]octan-6-yl)-17-imino-3,6-dimethyl-6,7,8,9,10,11,12a,13,14,15- decahydro-12H,17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17-oxide;(6R, 12aS, 17S)-11 -((3R,6s)-1 , 1 -Difl uorospi ro[2 ,5]octan-6-yl)-3, 6-di methyl- 17-(methylimino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-py rido[2,3-b]py rrolo[ 1 ,2- e][1 ]oxa[4]thi a[5, 8]d i azacyclotrideci n-12-one 17-oxide;(6R, 1 1 aS)-10-((3R,6s)-1 , 1 -D if I uorospiro[2.5]octan-6-y l)-3, 6-d i methy I-7, 8, 9, 10, 1 1 a, 12, 13, 14-octahydropyrido[2,3- b]pyrrolo[ 1 , 2-e][ 1 ]oxa[4]thi a[5, 8]di azacyclododeci n- 11 (6H)-one 16, 16-dioxide;(6R, 12aS)-11 -(4,4-Dif I uorocyclohexy l)-3, 6-di methyl-6, 7, 8, 9, 10, 1 1 , 12a, 13, 14, 15-decahydro-12H-pyrido[2,3- b]pyrrolo[ 1 , 2-e][ 1 ]oxa[4]thi a[5, 8]di azacyclotrideci n- 12-one 17, 17-dioxide;(6R, 12aS)-11 -((3 R,5s)-1 , 1 -D if I uorospiro[2.3]hexan-5-y l)-3, 6-d i methy I-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H- pyrido[2,3-b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-12-one 17, 17-dioxide;(1 R,4s)-4-((6R, 12aS)-3,6-Dimethyl-17, 17-dioxido-12-oxo-7,8,9,10, 12a,13, 14, 15-octahydro-6H-pyrido[2,3- b]pyrrolo[1,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11 (12H)-yl)-1-methylcyclohexane-1 -carbonitrile; or (1 R,4s)-4-((6R, 12aS)-4-FI uoro-3, 6-d imethy I- 17, 17-d ioxido- 12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro-6H- benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin-11 (12H)-yl)-1 -methylcyclohexane-1 -carbonitrile;(6R, 12aS, 17S)-1 1 -((3R,6s)-1 , 1 -Difl uorospi ro[2 ,5]octan-6-yl)-3, 6-di methyl- 17-(methylimino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin- 12-one 17-oxide;(6R, 12aS, 17S)-11 -((3R,6s)-1 , 1 -D if luorospiro[2.5]octan-6-yl)-3, 6-di methy I- 17-((methyl-d3)imino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1]oxa[4]thia[5,8]diazacyclotridecin- 12-one 17-oxide;(12S,51S,53S,2R)-8-((3R,6s)-1 , 1 -Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cyclohexanacyclononaphan-9-one 2-oxide;(12S,51R,53R,2S)-8-((3R,6s)-1 ,1 -Difluorospiro[2.5]octan-6-yl)-2-imino-36-methyl-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cyclohexanacyclononaphan-9-one 2-oxide (1 R,4s)-1 -Methyl-4-((12S,51R,53R,2S)-36-methyl-2-(methylimino)-2-oxido-9-oxo-2λ6-4-oxa-2λ6-thia-8-aza-3(3,2)- pyridina-1 (1 ,2)-pyrrolidina-5(1 ,3)-cydohexanacyclononaphane-8-yl)cyclohexane-1 -carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro-6H, 17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e][1 ]oxa[4]thia[5,8]diazacyclotridecin-1 1 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1 ]oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((8R, 12aS, 17S)-3,8-Dimethyl-17-(methylimino)-17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-benzo[b]pyrrolo[1 ,2-e][1 ]oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-1 -Methyl-4-((12S,51R,53R,2S)-34-methyl-2-(methylimino)-2-oxido-9-oxo-2λ6-4-oxa-2λ6-thia-8-aza-1 (1 ,2)- pyrrolidina-3(1 ,2)-benzena-5(1 ,3)-cyclohexanacyclononaphane-8-yl)cyclohexane-1 -carbonitrile;(1 R,4s)-1-Methyl-4-((6R,8R, 12aS, 17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-0X0-7,8,9, 10, 12a, 13, 14, 15- octahydro-6H, 17H-17λ- -benzo[b]pyrrolo[1 , 2-e][ 1 ]oxa[4]th i a[5,8]d iazacyclotrideci n- 11 ( 12H )-y IJcyclohexane- 1 - carbonitrile;(6R, 12aS, 17S)-11 -((3R,6s)-1 , 1 -D if luorospiro[2.5]octan-6-yl)-3, 6-di methyl- 17-((methyl-d3)imino)-6, 7, 8, 9, 10, 11 , 12a, 13, 14, 15-decahydro-12H, 17H-17λ4-py rido[2,3-b]py rroloj 1 ,2- e][1 ]oxa[4]thi a[5, 8]d i azacyclotrideci n-12-one 17-oxide;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17λ4-pyrido[2,3-b]pyrrolo[1 ,2-e][1 ]oxa[4]thia[5,8]diazacyclotridecin-1 1 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((6R, 12aS, 17S)-3,6-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17 / ?-benzo[b]pyrrolo[1 ,2-e][1 ]oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-4-((8R, 12aS, 17S)-3,8-Dimethyl-17-((methyl-d3) i mino)- 17-oxido-12-oxo-7,8,9, 10, 12a, 13, 14, 15-octahydro- 6H, 17H-17 / ?-benzo[b]pyrrolo[1 ,2-e][1 ]oxa[4]th i a[5,8]d i azacyclotrideci n- 11 (12H)-yl)-1 -methylcyclohexane-1 - carbonitrile;(1 R,4s)-1-Methyl-4-((6R,8R, 12aS, 17S)-3,6,8-trimethyl-17-(methylimino)-17-oxido-12-0X0-7,8,9, 10, 12a, 13, 14, 15- octahydro-6H, 17H-17λ4-py rido[2,3-b]py rroloj 1 ,2-e][1 ]oxa[4]th i a[5, 8]d i azacyclotrideci n- 1 1 (12H )-y IJcyclohexane- 1 - carbonitrile; or(1 R,4s)-4-((6R, 12aS)-6-Ethyl-3-methy I- 17, 17-d ioxido- 12-oxo-6,7,9, 10, 12a, 13, 14, 15-octahydropyrido[2,3- e]pyrrolo[1 ,2-h][1 ,4]dioxa[7]thia[8, 11 ]diazacyclotridecin-1 1 (12H)-yl)-1-methylcyclohexane-1-carbonitrile; or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament.

13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in improving wakefulness.

14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof:• for use in the treatment of hypersomnia including narcolepsy, narcolepsy associated with inherited disorders; narcolepsy associated with tumors, narcolepsy associated with head trauma, idiopathic hypersomnia, or Kleine-Levin syndrome;• for use in improving symptoms of excessive daytime sleepiness (EDS) including: o improving symptoms of EDS in subjects having a circadian rhythm sleep-wake disorder;o improving symptoms of EDS due to or associated with a medical disorder, wherein 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; o improving symptoms of EDS due to a medication or substance;• for use in the treatment of eating disorders, obesity, neuropsychiatric disorders, pain, inflammation, or cognitive impairments associated with diminished wakefulness; or• for the use in treatment of fatigue including: o improving symptoms of fatigue accompanied by poor concentration and memory; o improving symptoms of chronic fatigue associated with cancer or chemotherapy; o improving symproms of chronic fatigue associated with infections, (chronic) inflammatory diseases, autoimmune diseases or neurological diseases; o treatment of chronic fatigue associated with myalgic encephalomyelitis / chronic fatigue syndrome;• for use in improving symptoms of cognitive impairment including age-related cognitive disorders;• for use in the treatment of attention deficit including attention-deficit hyperactivity disorder; or• for use in the treatment of mood disorders associated with reduced hedonic drive including depression, schizophrenia, or addiction.

15. Use of a compound of Formula (I) as defined in any one of claims 1 to 10, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for improving wakefulness.

16. A method for improving wakefulness comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) as defined in any one of claims 1 to 10, or of a pharmaceutically acceptable salt thereof.